UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
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FORM 8-K
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CURRENT REPORT
Pursuant to Section 13 or 15(d)
of the Securities Exchange Act of 1934
Date of Report (Date of earliest event reported): December 11, 2022
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(Exact name of registrant as specified in its charter)
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(State or other jurisdiction of incorporation) | (Commission File Number) | (IRS Employer Identification No.) | ||||||||||||
(Address of principal executive offices including zip code)
Registrant’s telephone number, including area code: (650 ) 382-3281
(Former name or former address, if changed since last report)
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Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions:
| Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425) | |||||
| Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12) | |||||
| Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b)) | |||||
| Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c)) | |||||
Securities registered pursuant to Section 12(b) of the Act:
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Indicate by check mark whether the registrant is an emerging growth company as defined in Rule 405 of the Securities Act of 1933 (§230.405 of this chapter) or Rule 12b-2 of the Securities Exchange Act of 1934 (§240.12b-2 of this chapter).
Emerging growth company ☒
If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ☒
Item 8.01 Other Events.
On December 11, 2022, Senti Biosciences, Inc., (the “Company”) issued a press release announcing a presentation at the American Society of Hematology (“ASH”) annual meeting in New Orleans. Copies of the press release and the presentation slide deck presented at the ASH annual meeting are filed herewith as Exhibits 99.1 and 99.2 to this Current Report on Form 8-K and incorporated by reference herein.
The Company has also updated certain corporate information in a presentation slide deck. A copy of this corporate presentation is filed herewith as Exhibit 99.3 to this Current Report on Form 8-K and incorporated by reference herein.
Cautionary Statement
This filing and the exhibits include “forward-looking statements” within the meaning of Section 27A of the Securities Act of 1933, as amended (the “Securities Act”), and Section 21E of the Securities Exchange Act of 1934, as amended (the “Exchange Act”). We intend these forward-looking statements to be covered by the safe harbor provisions for forward-looking statements contained in Section 27A of the Securities Act and Section 21E of the Exchange Act, and are making this statement for purposes of complying with those safe harbor provisions. These forward-looking statements reflect our current views about our plans, intentions, expectations, strategies, and prospects, which are based on the information currently available to us and on assumptions we have made. Important factors that may cause actual results to differ materially from those described in the forward-looking statements are disclosed in the respective exhibits and in the “Risk Factors” contained in the Company’s Form 10-Q filed with the Securities and Exchange Commission (the “Commission”) on November 10, 2022, and other filings we make with the Commission. All forward-looking statements are expressly qualified in their entirety by such factors. We do not undertake any duty to update any forward-looking statement except as required by law.
Item 9.01 Financial Statements and Exhibits.
(d) Exhibits
| Exhibit No. | Description | |||||||
| 99.1 | ||||||||
| 99.2 | ||||||||
| 99.3 | ||||||||
| 104 | Cover Page Interactive Data File (embedded within the Inline XBRL document) | |||||||
SIGNATURE
Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
| SENTI BIOSCIENCES, INC. | |||||||||||||||||
| Date: | December 12, 2022 | By: | /s/ Timothy Lu | ||||||||||||||
| Name: | Timothy Lu, M.D., Ph.D. | ||||||||||||||||
| Title: | Chief Executive Officer & President | ||||||||||||||||
Senti Bio Highlights Preclinical Data from Logic-Gated Gene Circuit CAR-NK Cell Therapy SENTI-202
at ASH Annual Meeting and Investor Event
– ASH poster presentation summarizes preclinical data from SENTI-202, an off-the-shelf CAR-NK cell therapy candidate engineered with a logic-gated gene circuit and multi-armed with crIL-15, that is advancing toward clinical development for hematologic malignancies –
– SENTI-202 is on track for IND filing in 2H 2023 –
– SENTI-202 aims to more precisely target tumor cells in CD33 and/or FLT3 expressing tumors such as acute myeloid leukemia and myelodysplastic syndrome, while sparing healthy cells –
– Senti Bio Investor Event to include an AML expert; in-person and webcast at 12:30 p.m. ET/11:30 a.m. CT today –
NEW ORLEANS, La., December 11, 2022 — Senti Biosciences, Inc. (Nasdaq: SNTI) (“Senti Bio”), a biotechnology company innovating next-generation cell and gene therapies using its proprietary gene circuit platform, today announced a presentation at the American Society of Hematology (ASH) Annual Meeting in New Orleans. The presentation highlights preclinical data that led to the selection of SENTI-202 as the Company's lead oncology candidate. Senti Bio plans to evaluate SENTI-202 in patients with CD33 and/or FLT3 expressing hematologic malignancies including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), with an anticipated filing of an Investigational New Drug (IND) application in the second half of 2023.
“The preclinical data presented at ASH demonstrates the progress made with our lead logic-gated gene circuit CAR-NK cell therapy, SENTI-202, which incorporates our OR gate, NOT gate, and calibrated release IL-15 technologies," said Tim Lu, MD, PhD, Chief Executive Officer and Co-Founder of Senti Bio. "In both in vitro and in vivo models, we observed that SENTI-202 had significant and precise cancer-killing activity against AML, and significant protection of healthy cells from off-tumor cytotoxicity. We are hopeful that these preclinical results will translate into the clinic for patients with AML and MDS. The success of these gene circuits in the clinic would broadly enable off-the-shelf CAR-NK cells that precisely kill cancer cells while sparing healthy cells across multiple tumor indications."
In addition to Senti Bio presenting these data and the initial SENTI-202 clinical development plan, today’s Investor Event will also feature a presentation by Stephen A. Strickland, Jr., MD, MSCI, Director of Leukemia Research for the Sarah Cannon Transplant & Cellular Therapy Network, who will review the current treatment landscape as well as the potential role for next-generation cell therapies in AML and MDS.
"I am excited about the potential for next-generation cell therapies, like SENTI-202, to target multiple disease pathways to overcome the often harsh tumor microenvironment and provide enhanced cancer-killing activity," said Dr. Strickland. "The outcome for patients with AML is poor, with a 5 year relative survival rate of approximately 30% at diagnosis and 5 month overall survival when relapsed/refractory1. New therapies with novel mechanisms of action are needed to combat this aggressive disease. I look forward to seeing possible improved treatment for patients and am hopeful that these novel technologies can enable greater tumor clearance with less off-tumor toxicity, and ultimately deeper and longer remissions."
SENTI-202, a Selective, Off-the-Shelf, Preclinical CAR-NK Cell Therapy with CD33 and/or FLT3 Activating CAR, Healthy Cell Protection from Endomucin (EMCN) Inhibitory CAR and Calibrated Release IL-15 for Hematologic Malignancies Including AML, Garrison et al. (Poster presentation: December 10, 2022)
New preclinical data for SENTI-202 were presented supporting Senti Bio’s approach of using an OR Gate to provide robust targeting of AML disease (blasts and leukemic stem cells (LSCs)), and a NOT Gate to protect healthy hematopoietic stem cells (HSCs) from off-tumor toxicity.
•SENTI-202 demonstrated significant aCAR-mediated anti-tumor activity, including in vivo tumor suppression in an AML xenotransplantation model, and significant in vitro killing of primary AML blasts and LSCs from patient samples. Targeting AML LSCs is believed to be essential for achieving longer-lasting remissions and/or curative outcomes and is, the Company believes, a potentially significant differentiating aspect of SENTI-202 compared to available therapies.
•SENTI-202 demonstrated significant iCAR-mediated in vitro protection of primary healthy donor EMCN+ HSCs from off-tumor toxicity, and significant in vivo protection of EMCN+ model healthy cells from off-tumor toxicity. HSCs are responsible for lifelong hematopoiesis, and protecting them from off-tumor toxicity may broaden the therapeutic window for SENTI-202, enabling more precise and potentially more effective treatment.
•SENTI-202 demonstrated sufficient crIL-15 expression to activate the IL-15 receptor pathway, shown to result in increased CAR-NK cell persistence and killing activity.
The SENTI-202 poster is available on the Senti Bio website.
To access the Investor Event via webcast, please visit the Events & Presentations page on the Senti Bio website.
1. Am J Blood Res. 2020 Aug 25;10(4):124-133. eCollection 2020. https://pubmed.ncbi.nlm.nih.gov/32923092/
About Senti Bio
Our mission is to create a new generation of smarter medicines that outmaneuver complex diseases using novel and unprecedented approaches. To accomplish this, we are building a synthetic biology platform that may enable us to program next-generation cell and gene therapies with what we refer to as Gene Circuits. These novel and proprietary Gene Circuits are designed to reprogram cells with biological logic to sense inputs, compute decisions and respond to their cellular environments. We aim to design Gene Circuits to improve the intelligence of cell and gene therapies in order to enhance their therapeutic effectiveness, precision, and durability against a broad range of diseases that conventional medicines do not readily address.
Our synthetic biology platform utilizes off-the-shelf chimeric antigen receptor natural killer (CAR-NK) cells, outfitted with Gene Circuit technologies, to target particularly challenging liquid and solid tumor oncology indications. Our lead product candidate is SENTI-202 for the treatment of CD33 and/or FLT3 expressing hematologic malignancies, such as AML and MDS. We are developing an additional CAR-NK product candidate, SENTI-301A, for the treatment of hepatocellular carcinoma (HCC) and other GPC3 positive cancers. We also have a CAR-NK program for the treatment of colorectal cancer (CRC) and other CEA positive cancers, SENTI-401. We have also demonstrated the breadth of our Gene Circuits in other modalities and diseases outside of oncology and have executed partnerships with Spark Therapeutics and BlueRock Therapeutics to advance these capabilities.
Forward-Looking Statements
This document contains certain statements that are not historical facts and are considered forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended. These forward-looking statements generally are identified by the words “believe,” “could,” “predict,” “continue,” “ongoing,” “project,” “expect,” “anticipate,” “explore,” “estimate,” “intend,” “strategy,” “future,” “opportunity,” “plan,” “may,” “should,” “will,” “would,” “will be,” “will continue,” “will likely result,” “forecast,” “seek,” “target” and similar expressions that predict or indicate future events or trends or that are not statements of historical matters. Forward-looking statements are predictions, projections and other statements about future events that are based on current expectations of Senti Bio’s management and assumptions, whether or not identified in this document, and, as a result, are subject to risks and uncertainties. Forward-looking statements include, but are not limited to, statements regarding Senti Bio’s research and development activities, including the development of product candidates, progress of IND-enabling studies and the timing of submission of IND filings, plans for advancing SENTI-202 into the clinic, presentation plans at the Investor Event, as well as statements about the potential attributes and benefits of Senti Bio’s product candidates, including their clinical and therapeutic potential, and Senti Bio’s platform technology. These forward-looking statements are provided for illustrative purposes only and are not intended to serve as, and must not be relied on as a guarantee, an assurance, a prediction or a definitive statement of fact or probability. Many actual events and circumstances are difficult or impossible to predict, are beyond the control of Senti Bio and will differ from assumptions. Many factors could cause actual future events to differ materially from the forward-looking statements in this document, including but not limited to the risk that results observed in studies of its product candidates, including preclinical studies and future clinical trials of any of its product candidates, will not be observed in ongoing or future studies involving these product candidates, the risk that Senti Bio may cease or delay clinical development of any of its product candidates for a variety of reasons (including requirements that may be imposed by regulatory authorities on the initiation or conduct of clinical trials, the amount and type of data to be generated, or otherwise to support regulatory approval, difficulties or delays in subject enrollment and continuation in current and planned clinical
trials, difficulties in manufacturing or supplying Senti Bio’s product candidates for preclinical and clinical testing, and any adverse events or other negative results that may be observed during preclinical or clinical development), Senti Bio’s ability to obtain, maintain and protect its intellectual property, Senti Bio’s dependence on third parties for development and manufacture of product candidates, Senti Bio’s ability to manage expenses and to obtain additional funding when needed to support its business activities and establish and maintain strategic business alliances and new business initiatives, the impacts of macroeconomic and geopolitical events, including changing conditions from the COVID-19 pandemic, the hostilities in Ukraine, increasing rates of inflation and rising interest rates on business operations and expectation, and the risk that its product candidates may not produce therapeutic benefits or may cause other unanticipated adverse effects. The foregoing list of factors is not exhaustive. You should carefully consider the foregoing factors and the other risks and uncertainties described in the “Risk Factors” section of Senti Bio’s Form 10-Q filed with the SEC on November 10, 2022, and other documents filed by Senti Bio from time to time with the SEC. These filings identify and address other important risks and uncertainties that could cause actual events and results to differ materially from those contained in the forward-looking statements in this document. There may be additional risks that Senti Bio does not presently know, or that Senti Bio currently believes are immaterial that could also cause actual results to differ from those contained in the forward-looking statements in this document. Forward-looking statements speak only as of the date they are made. Senti Bio anticipates that subsequent events and developments may cause Senti Bio’s assessments to change. Except as required by law, Senti Bio assumes no obligation to update publicly any forward-looking statements, whether as a result of new information, future events, or otherwise.
Availability of Other Information About Senti Bio
For more information, please visit the Senti Bio website at https://www.sentibio.com or follow Senti Bio on Twitter (@SentiBio) and LinkedIn (Senti Biosciences). Investors and others should note that we communicate with our investors and the public using our company website (www.sentibio.com), including, but not limited to, company disclosures, investor presentations and FAQs, Securities and Exchange Commission filings, press releases, public conference call transcripts and webcast transcripts, as well as on Twitter and LinkedIn. The information that we post on our website or on Twitter or LinkedIn could be deemed to be material information. As a result, we encourage investors, the media and others interested to review the information that we post there on a regular basis. The contents of our website or social media shall not be deemed incorporated by reference in any filing under the Securities Act of 1933, as amended.
Senti Bio Contacts:
Investors:
investors@sentibio.com
Media:
Kelli Perkins
kelli@redhousecomms.com
Find more information at sentibio.com
Follow us on Linkedin: Senti Biosciences
Follow us on Twitter: @SentiBio
™ D E C E M B E R 2 0 2 2 IN V E ST O R E V E N T | SE N T I B IO SC IE N C E S Investor Event 1 December 2022
D E C E M B E R 2 0 2 2 IN V E ST O R E V E N T | SE N T I B IO SC IE N C E S Disclaimer 2 Forward Looking Statements This presentation contains forward-looking statements. Statements we make in this presentation may include statements which are not historical facts and are considered forward-looking within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended, which are usually identified by the use of words such as “anticipates,” “believes,” “estimates,” “expects,” “future,” “opportunity,” “proposed,” “targets,” “intends,” “may,” “plans,” “projects,” “seeks,” “should,” “will,” and variations of such words or similar expressions. We intend these forward-looking statements to be covered by the safe harbor provisions for forward-looking statements contained in Section 27A of the Securities Act and Section 21E of the Securities Exchange Act and are making this statement for purposes of complying with those safe harbor provisions. These forward-looking statements, including statements relating to the attributes and benefits of our technology platform and our product candidates, including their clinical and therapeutic potential which may fill existing treatment gaps, our plans to provide further pre-clinical data updates and the related timing, our plans to submit an IND for SENTI-202 and the related timing, our proposed Phase 1 study, including study design and endpoints, our manufacturing process and its potential benefits, our plans to buildout our cGMP facility and the related timing, and our cash position and runway, reflect our current views about our plans, intentions, expectations, strategies and prospects, which are based on the information currently available to us and on assumptions we have made. These forward-looking statements are provided for illustrative purposes only and are not intended to serve as, and must not be relied on as a guarantee, an assurance, a prediction or a definitive statement of fact or probability. Although we believe that our plans, intentions, expectations, strategies and prospects as reflected in or suggested by those forward-looking statements are reasonable, we can give no assurance that the plans, intentions, expectations or strategies will be attained or achieved. Many actual events and circumstances are difficult or impossible to predict, are beyond our control and will differ from assumptions. Furthermore, actual results may differ materially from those described in the forward-looking statements and will be affected by a variety of risks and factors that are beyond our control including, without limitation, the risk that results observed in studies of our product candidates, including preclinical studies and future clinical trials of any of our product candidates, will not be observed in ongoing or future studies involving these product candidates, the risk that we may cease or delay clinical development of any of our product candidates for a variety of reasons (including requirements that may be imposed by regulatory authorities on the initiation or conduct of clinical trials, the amount and type of data to be generated, or otherwise to support regulatory approval, difficulties or delays in subject enrollment and continuation in current and planned clinical trials, difficulties in manufacturing or supplying our product candidates for preclinical and clinical testing, and any adverse events or other negative results that may be observed during preclinical or clinical development), our ability to obtain, maintain and protect our intellectual property, our dependence on third parties for development and manufacture of product candidates, our ability to manage expenses and to obtain additional funding when needed to support our business activities and establish and maintain strategic business alliances and new business initiatives, the impacts of macroeconomic and geopolitical events, including changing conditions from the COVID-19 pandemic, the hostilities in Ukraine, increasing rates of inflation and rising interest rates on business operations and expectation, and the risk that our product candidates may not produce therapeutic benefits or may cause other unanticipated adverse effects, as well as those set forth in the section titled “Risk Factors” in our Form 10-Q filed with the Securities and Exchange Commission (“SEC”) on November 10, 2022, and our subsequent SEC filings. Except as required by law, we assume no obligation to update publicly any forward-looking statements, whether as a result of new information, future events or otherwise. Trademarks This document contains references to trademarks, trade names and service marks belonging to other entities. Solely for convenience, trademarks, trade names and service marks referred to in this presentation may appear without the ® or TM symbols, but such references are not intended to indicate, in any way, that the applicable owner will not assert, to the fullest extent under applicable law, its rights to these trademarks and trade names. We do not intend our use or display of other entities’ trade names, trademarks or service marks to imply a relationship with, or endorsement or sponsorship of us by, any other entities.
D E C E M B E R 2 0 2 2 IN V E ST O R E V E N T | SE N T I B IO SC IE N C E S Agenda 3 Gene Circuits to Engineer Next Generation Cell Therapies Tim Lu, MD, PhD – Co-founder & CEO Treatment Paradigm and Unmet Medical Need in AML Stephen A. Strickland, Jr., MD, MSCI - Director of Leukemia Research at the Sarah Cannon Transplant & Cellular Therapy Network Update on SENTI-202 For Heme Malignancies Kanya Rajangam, MD, PhD – Chief Medical and Development Officer (CMDO) Conclusions and Next Steps Tim Lu, MD, PhD – Co-founder & CEO Q&A
D E C E M B E R 2 0 2 2 IN V E ST O R E V E N T | SE N T I B IO SC IE N C E S Gene Circuits to Engineer Next Generation Cell Therapies Tim Lu, MD, PhD - Co-founder & CEO 4
D E C E M B E R 2 0 2 2 IN V E ST O R E V E N T | SE N T I B IO SC IE N C E S Senti’s Next Generation Gene Circuit Technologies for Cancer Cell Therapy 5 Broaden patient access Address efficacy AND safety Address large unmet needs across multiple solid and liquid tumors Enhance durability and persistence Increase specificity and dosing window Aim to.. NK Cells Logic Gating Regulator DialMulti-Arming Can be applied to: T Cells HSCsiPSCs Gene Circuits for Cell Therapy: NK Cells: Natural Killer Cells, iPSCs: induced pluripotent stem cells, HSCs: hematopoietic stem cells
D E C E M B E R 2 0 2 2 IN V E ST O R E V E N T | SE N T I B IO SC IE N C E S Today’s Cell Therapies Are Largely Guided by Single CAR System and Limited to a Small Set of Potential Therapeutic Targets 6 Only ~5% of potential surface proteins have been utilized in CAR therapies Heterogeneous antigen expression leading to tumor escape On-target / off-tumor killing leading to poor therapeutic window Two key limitations of today’s cell therapies
D E C E M B E R 2 0 2 2 IN V E ST O R E V E N T | SE N T I B IO SC IE N C E S Senti’s Gene Circuit Technology Has the Potential to Expand the Range of CAR Cell Therapies With Enhanced Efficacy and Precision 7 Expanding the range of potential therapeutics into the “empty” space Inhibitory CAR: NOT GATESenti’s next-gen capabilities Bivalent activating CAR: OR GATE
D E C E M B E R 2 0 2 2 IN V E ST O R E V E N T | SE N T I B IO SC IE N C E S Gene Circuits Designed to Solve for Key Cell Therapy Challenges 8 Senti’s Gene Circuit Solutions Cancer Cell Therapy Challenges Lack of NK cell expansion and persistence Antigen escape and tumor heterogeneity Dirty targets (on-target / off-tumor toxicity) Immunosuppressive tumor microenvironment Multi-Arming Autocrine and paracrine activation with proprietary Calibrated Release IL-15 (crIL-15) and other complementary cytokines (e.g., IL-21) Bivalent activating CAR with OR Logic GateLogic Gating Inhibitory CAR protects healthy cells with NOT Logic GateLogic Gating Pulsed Calibrated Release IL-12 with small molecule- controlled Regulator Dial Regulator Dial
D E C E M B E R 2 0 2 2 IN V E ST O R E V E N T | SE N T I B IO SC IE N C E S NK Cells Compare Favorably to T Cell Based Therapies, While Gene Circuits Have Potential to Further Improve Efficacy, Safety, and Durability Further 9 NK cells are an attractive modality vs T cells • Extensive clinical experience with ~70 global peripheral blood derived unengineered NK cell therapy clinical trials1 • Well-tolerated with no/minimal CRS, neurotoxicity, GvHD • Anti-tumor activity including CR observed in R/R AML Key limitations noted with prior unengineered NK cell therapies • Limited persistence • Limited ability to cryopreserve • Scale-up manufacture Senti’s Gene Circuit technology, donor selection and scalable manufacturing aim to address these limitations Capabilities Current Auto T Cells Off-the-shelf potential with broad patient accessibility Designed with Logic Gates to achieve enhanced selectivity and safety Engineered with enhanced persistence N/A ✓ ✓ ✓ Senti’s CAR-NK Cells Engineered to stimulate the patient immune system ✓ 1 Lamers-Kok Journal of Hematology & Oncology 2022 CRS: cytokine release syndrome, GvHD: graft-versus-host disease, AML: acute myeloid leukemia
D E C E M B E R 2 0 2 2 IN V E ST O R E V E N T | SE N T I B IO SC IE N C E S Senti’s Next Generation CAR-NK Cell Therapy Pipeline Tackles Hard to Treat Cancers With Gene Circuits 10 Program Target Indications Discovery IND enabling Phase 1 Gene Circuits SENTI-202 CD33 and/or FLT3 AML, MDS and other blood cancers ✓ Multi-Arming: designed for enhanced efficacy ✓ crIL-15: autocrine and paracrine activation ✓ OR GATE: bivalent activation ✓ NOT GATE selectivity: healthy cell protection SENTI-301A GPC3 HCC and other solid tumors ✓ Multi-Arming: designed for enhanced efficacy ✓ crIL-15: autocrine and paracrine activation SENTI-401 CEA CRC and other solid tumors ✓ Multi-Arming: designed for enhanced efficacy ✓ crIL-15: autocrine and paracrine activation ✓ NOT GATE selectivity: healthy cell protection ✓ IL-21: sustained anti-tumor function Additional Programs Undisclosed Other tumors Program candidates integrate Multi-Arming, Logic Gating and/or Regulator Dial Gene Circuits 2023 IND 2024 IND 2H 2023 IND MDS: myelodysplastic syndromes, HCC: hepatocellular carcinoma, CRC: colorectal cancerr
D E C E M B E R 2 0 2 2 IN V E ST O R E V E N T | SE N T I B IO SC IE N C E S SENTI-202, a Novel, Multi-Armed, Off-The-Shelf, Selective CAR-NK Cell Therapy for Blood Cancers Including AML and MDS 11LSCs: Leukemic Stem Cells Multi-Armed, off-the-shelf, selective CAR-NK • OR GATE: bivalent CD33 and/or FLT3 activation → potential for deep and durable responses in acute myeloid leukemia (AML) and other blood cancers. • NOT GATE: inhibition by endomucin (EMCN) protective antigen selectively expressed on healthy hematopoietic stem cells (HSCs) → potential for improved safety and increased therapeutic window • crIL-15 → potential for increased persistence, autocrine and paracrine immune cell activation On track for IND in 2H 2023
D E C E M B E R 2 0 2 2 IN V E ST O R E V E N T | SE N T I B IO SC IE N C E S EMCN Engagement Enables Protection of Healthy HSCs FLT3 OR CD33 Engagement Triggers Killing of Heterogeneous AML Cancer Cells SENTI-202 Logic Gates Are Designed to Achieve Deep Clearance of AML Blasts and LSCs While Sparing Healthy HSCs 12 CD33 FLT3 EMCNAntigen: Healthy HSC SENTI-202 CAR-NK Cell Safety AntigenInhibitory CAR (iCAR)Tumor-Associated AntigensActivating CAR (aCAR) SENTI-202 CAR-NK Cell AML Cancer Cells Blast Cell LSC Do Not Kill
D E C E M B E R 2 0 2 2 IN V E ST O R E V E N T | SE N T I B IO SC IE N C E S crIL-15 Senti’s Proprietary crIL-15 Technology Aims to Enhances NK Cell Expansion, Persistence and Tumor Killing 13 1. CYTOKINE SECRETION ONLY (PARACRINE) Enhanced NK Cell Expansion, Persistence and Tumor Killing 3. CALIBRATED RELEASE (cr) (PARACRINE AND AUTOCRINE) Cell Therapies Using This Approach Combines 1 & 2 2. MEMBRANE-BOUND ONLY (AUTOCRINE) Secreted IL-15 can activate neighboring immune cells present in the local tumor microenvironment (TME) • Secreted IL-15 activates neighboring immune cells present in the local TME • Membrane-bound IL-15 on the cell surface increases NK cell activity/function Membrane-bound IL-15 on the cell surface leads to autocrine activity and increases CAR-NK cell activity/function IL-15 Membrane bound IL-15
D E C E M B E R 2 0 2 2 IN V E ST O R E V E N T | SE N T I B IO SC IE N C E S Scalable Manufacturing to Support Off-The-Shelf CAR-NK Products 14 Lentivi rus Outpatient use potential Patient Isolate from selected donors Thaw and infuse Scalable ~21 Day Process NK Cells Selected Donor Gene Circuit Engineered CAR-NK cells Engineer CryopreserveExpand Off-The-Shelf Gene Circuits 1 2 3 4 5 Easy to thaw vials Final product harvested and cryopreserved >100 doses per batch NK cells isolated from peripheral blood of selected donors NK cells efficiently engineered with Gene Circuits High post-thaw potency
D E C E M B E R 2 0 2 2 IN V E ST O R E V E N T | SE N T I B IO SC IE N C E STreatment Paradigm and Unmet Medical Need in AML Stephen A. Strickland, Jr., MD, MSCI - Director of Leukemia Research at the Sarah Cannon Transplant & Cellular Therapy Network 15
DO NOT DISTRIBUTE 1973 Cytarabine/ Daunorubicin (7+3) 2000 Gemtuzumab ozogamicin 1977 First bone marrow transplant 2002 Idarubicin 2017 Midostaurin, Gemtuzumab ozogamicin (re- approved), CPX- 351, Enasidenib 2010 Gemtuzumab ozogamicin (withdrawal) 2018 Ivosidenib, Gilteritinib, Venetoclax, Glasdegib 2020 Azacitidine (maintenance) History of FDA Approvals in AML: Small molecules against broad targets/pathways ADCs Monoclonal antibodies Cell therapies or immune cell engagers directed at AML cells Over 600 clinical trials recruiting in AML using various modalities: Cell therapies designed to improve transplant outcomes VaccinesRadiopharmaceuticals Small molecules for genetically defined subsets History of FDA Approvals and Current Clinical Trials in AML
DO NOT DISTRIBUTE Significant Unmet Need in AML Even with Recent Approvals 1 Clarivate source data 2022; 2 Mangan Ther Adv Hematology 2011; 3 Brandwein Figure from Brandwein Am J Blood 2020 5.3 months median OS 12.6% 5-year OS AML • ~14,000 patients are newly diagnosed with AML in the US1 • Treatment at diagnosis generally includes intensive chemotherapy consolidated with HCT for younger fitter patients, and hypomethylating agents with venetoclax for older unfit patients • Even with initial intensive treatment, 20-40% of patients fail to respond to up-front AML therapy while ~50% of those who attain an initial CR eventually relapse2 • Prognosis at relapse is grim with ~5-10 months overall survival in R/R AML patients and limited standard of care options that includes FLT3, IDH1/2 inhibitors if relevant mutations are present3
DO NOT DISTRIBUTE AML Is a Heterogenous Disease and Requires Multi-Antigen Targeting SC-DARIC-33 JEZ-567 PRGN-3006 Targets Expressed on AML Blasts And/Or LSCs ICG-144 Target Antigen Expression on Various Cells1 Antigen LSCs Blasts HSCs CD33 (SIGLEC3) +/- + +/- FLT3 (CD135) + +/- + CLL-1 (CLEC12A) +/- + - CD123* +/- + +/- CD38 - + - NKG2D ligands - + - AML targets are notoriously heterogenous: CAR targets in AML and CAR cell therapies currently in clinical trials2: Targeting LSCs Is Critical in the Treatment of AML but Most CAR-Based Therapies Target Only One Antigen Leading To Incomplete Clearance of Leukemic Blasts and Stem Cells (LSCs), Tumor Escape and Eventual Patient Relapse 1 Valent Stem Cell Trans. Med. 2020, 2 Marvin-Peek Cancers 2022 * Note: CD123 is highly expressed in endothelial cells
DO NOT DISTRIBUTE The Need to Limit On-Target / Off-Tumor Toxicity in AML ESAs = Erythropoiesis-stimulating agents, G-CSF = Granulocyte colony stimulating factor Myelosuppression Anemia Thrombocytopenia Neutropenia Consequence Fatigue Risk of bleeding Risk of infection Targeting HSPCs leads to… • Common AML targets are largely expressed on cancer cells AND healthy hematopoietic stem and progenitor (HSPC) cells leading to on-target, off-tumor toxicity • Targeting HSPCs results in prolonged aplasia and myelosuppression leading to anemia, thrombocytopenia, neutropenia, and attendant complications like bleeding and infections • There is an urgent need for novel AML therapies with minimal bone marrow toxicities from off tumor effects CD123 CD123 CLL-1 Leukemic stem cells (LSCs) Leukemic blast cells Hematopoietic stem cell (HSC) Multipotent progenitor (MPP) cell Common lymphoid progenitor (CLP) cell Common myeloid progenitor (CMP) cell
D E C E M B E R 2 0 2 2 IN V E ST O R E V E N T | SE N T I B IO SC IE N C E SUpdate on SENTI-202 For Heme Malignancies Kanya Rajangam, MD, PhD - CMDO 20
D E C E M B E R 2 0 2 2 IN V E ST O R E V E N T | SE N T I B IO SC IE N C E S SENTI-202 for CD33 and/or FLT3 Expressing Blood Cancers Including AML 21 7,860 7 20,216 Protein Coding Genes 40 2,611 Membrane proteins High expression in AML Low non-hematopoietic expression Manual curation FLT3 and CD33 2,152 112 Confirm high AML expression Low healthy tissue expression Optimization for AML subpopulation coverage Proven Targets • FLT3 and/or CD33 expressed in ~95% of AML • Targeting FLT3 and CD33 with an OR GATE has potential of increased efficacy and deeper remission, due to decreased likelihood of tumor antigen escape • Rigorous bioinformatics approach was used to identify CD33 and FLT3 as an optimal aCAR pair to provide broad coverage of blasts and LSCs Bioinformatics approach to identify aCAR pair
D E C E M B E R 2 0 2 2 IN V E ST O R E V E N T | SE N T I B IO SC IE N C E S SENTI-202 Has Shown Robust Preclinical Anti-Tumor Activity 22 Vehicle Unengineered NK Cells SENTI-202 CAR- NK Cells Day: 7 28 34 Significant in vitro killing of leukemia cell line Robust suppression of tumor in AML MV4-11 xenotransplantation model Broad in vitro killing of primary AML and MDS tumor cells AML #1 0 10 20 30 40 50 60 70 80 90 100 Blasts LSCs Blasts LSCs Blasts LSCs Blasts % A M L/ M D S C el l K ill in g Unengineered NK Cells SENTI-202 CAR-NK Cells AML #2 AML #3 MDS 0 20 40 60 80 100 1:4 1:2 1:1 2:1 4:1 % C yt o to xi ci ty E:T Ratio Unengineered NK Cells SENTI-202 CAR-NK Cells
D E C E M B E R 2 0 2 2 IN V E ST O R E V E N T | SE N T I B IO SC IE N C E S Senti’s Discovery Platform Identified EMCN as a Key Protective Antigen for Healthy HSCs 23 Surface Protein 0% EMCN on primary AML LSCs EMCN Si d e Sc at te r (S SC ) 70% EMCN on primary HSCs Challenge Solution and Validation FLT3 is expressed on healthy HSCs 7,680 1 20,216 Protein Coding Genes 15 115 Membrane proteins High HSC/AML expression ratio Confirm low AML expression Manual curation EMCN The NOT GATE uses EMCN as a Protective Antigen input to differentiate between healthy HSCs and AML cells AML Blasts AML LSCs Neutrophils Healthy HSCs AML Blasts AML LSCs Neutrophils Healthy HSCs
D E C E M B E R 2 0 2 2 IN V E ST O R E V E N T | SE N T I B IO SC IE N C E S Senti’s Discovery Platform Identified LIR1 as the Optimal iCAR ICD for SENTI-202 24 Systematic approach to identify optimal iCAR ICD for SENTI-202 using a screen of native inhibitory proteins Anti-FLT3 scFV CD28 CD3ZH TM Native inhibitory receptors Native binding domains Anti-EMCN scFV Inhibitory domain H TM Native TM and inhibitor domains ITMs Activating CAR (aCAR) Inhibitory CAR (iCAR) On- tumor Off- tumor Comparative analysis between NOT gates with different iCAR ICDs identified LIR1 as optimal ICD for SENTI-202 On-target killing O ff -t u m o r ki lli n g 1- Screening and Identification of iCAR 2- Killing Assays 3- Logic Analysis Screen of anti-EMCN iCARs with various transmembrane and intracellular domains
D E C E M B E R 2 0 2 2 IN V E ST O R E V E N T | SE N T I B IO SC IE N C E S SENTI-202 Preclinical Selectivity via Inhibitory CAR Binding Endomucin to Protect Healthy Primary Human HSCs 25 In vitro protection of healthy primary human HSC fraction expressing EMCN 0 10 20 30 40 50 60 CD33 and/or FLT3 CAR-NK Cells SENTI-202 CAR-NK Cells % K ill in g (L e u ke m ia ) 0 5 10 15 20 25 30 35 40 45 50 CD33 and/or FLT3 CAR-NK Cells SENTI-202 CAR-NK Cells % K ill in g (E M C N + H SC s)
D E C E M B E R 2 0 2 2 IN V E ST O R E V E N T | SE N T I B IO SC IE N C E S SENTI-202 Preclinical Selectivity via EMCN iCAR Protects Model Healthy Cells In Vivo from aCAR-Mediated Killing 26 I.V. injection Blood draw After 27 days N o rm al iz e d C o u n ts N o rm al iz e d C o u n ts N o rm al iz e d C o u n ts Unengineered NK Cells OR Gated CAR-NK Cells SENTI-202 CAR-NK Cells SENTI-202 CAR-NK Cells “Healthy” Cells Cancer Cells50:50 “Healthy” Cells Spared Cancer Cells Killed
D E C E M B E R 2 0 2 2 IN V E ST O R E V E N T | SE N T I B IO SC IE N C E S Calibrated Release IL-15 (crIL-15) Increases Persistence and Activation of Both CAR-NK and Immune Cells in Tumor Milieu 27 0 2,000 4,000 6,000 sIL-15 CAR-NK crIL-15 CAR-NK Pa ra cr in e A ct iv it y (p ST AT 5 M FI ) Phospho STAT5 levels increased in T cells exposed to supernatant from either crIL-15 or sIL-15 CAR-NK cell culture crIL-15: IL-15 released by local proteases → autocrine and paracrine effects crIL-15 has paracrine activity and activates resting immune cells crIL-15 increases persistence of CAR- NK cells 0 0.2 0.4 0.6 0.8 1 0 5 10 15 20 25 V ia b le C el ls ( e6 ) Days in Culture crIL-15 increases CAR-NK serial killing compared to secreted IL-15 crIL-15 CAR-NK Cells Unengineered NK Cells sIL-15: secreted wild-type IL-15 0 1 2 3 4 5 0 1 2 3 4 5 6 7 8 9 Tu m o r C el l A b u n d an ce Days Vehicle Unengineered NK Cells crIL-15 CAR-NK Cells sIL-15 CAR-NK Cells Cancer cells added Cancer cells added Cancer cells added
D E C E M B E R 2 0 2 2 IN V E ST O R E V E N T | SE N T I B IO SC IE N C E S Proposed Phase 1 Study in R/R CD33+ And/or FLT3+ Malignancies With Focus on AML 28 Proposed Phase 1 study anticipated to enroll R/R CD33+ and/or FLT3+ heme malignancies • Modified “3+3” study design • Enroll patients who have received at least 1 prior treatment including targeted agents if FLT3, IDH1/2 mutation+ • 2 of 3 patients at each dose level with AML • Disease specific expansion cohorts for AML and MDS Planned study endpoints • Safety, DLT, identify recommended Phase 2 dose • Efficacy using standard ELN 2022 criteria for AML and other disease specific consensus criteria • PK, pharmacodynamics including endomucin protection, immunogenicity Lymphodepletion Fludarabine Cyclophosphamide SENTI-202 2-3 dose levels of cells Efficacy Additional cycles+ -5 to -3 0 7 14 28Days Planned Study Treatment/ Cycle Planned data- driven seamless Phase 1 to pivotal design
D E C E M B E R 2 0 2 2 IN V E ST O R E V E N T | SE N T I B IO SC IE N C E SConclusions and Next Steps Tim Lu, MD, PhD - Co-founder & CEO 29
D E C E M B E R 2 0 2 2 IN V E ST O R E V E N T | SE N T I B IO SC IE N C E S SENTI-202 Can Potentially Fulfill AML Treatment Gap 30 Multi-Arming Multi-Antigen Targeting Healthy Cell Protection Redosing Potential Scalable Manufacturing SENTI-202 Calibrated release IL-15 enhances NK cell expansion, persistence, and tumor killing Simultaneously targeting FLT3 and/or CD33 via Logic Gating to drive deeper clearance of AML blasts and LSCs and prevent antigen escape and patient relapse Protection of healthy HSCs via EMCN NOT Gate to minimize on-target/off-tumor toxicity, prevent myelosuppression and allow for repeat dosing Potential to increase durability and response by re- dosing patients Rigorous screening and selection of GMP donors to minimize variability
D E C E M B E R 2 0 2 2 IN V E ST O R E V E N T | SE N T I B IO SC IE N C E S SENTI-202 Aims to Fill Key Unmet Need of Targeting Both AML Blasts and AML LSCs 311 HSC toxicity was observed for several preclinical FLT3-targeted therapies, including CAR-T, ADCs and BiTes Select AML Cell Therapy Candidates in Development Manufacturer Modality MOA / Target1 Allogeneic CAR-T cells CD123 NKG2D ligands FLT3 OR CD33 NOT EMCN + + ✓ CAR-NK Cells iPSC-derived NK Cells CAR-NK Cells -- + Autologous CAR-T cells CLL-1 + Target Blasts +/- - ✓ - +/- Target LSCs We believe that by selectively targeting FLT3 (LSCs) and/or CD33 (blasts), we have the potential to provide AML patients with significantly deeper and longer remissions. Our clinical program initially enrolls patients with R/R CD33 and/or FLT3 positive heme malignancies with focus on AML with the potential to expand into earlier lines of therapy NKX101 FT538 UCART12 SENTI-202 KITE-222
D E C E M B E R 2 0 2 2 IN V E ST O R E V E N T | SE N T I B IO SC IE N C E S YTD Progress and Planned Milestones in the Next 12 Months 32 SENTI-202 IND in 2H 2023 Pre-clinical data updates from multiple CAR-NK programs planned at key scientific meetings in 2023 GMP facility buildout on track to enable clinical manufacturing of CAR-NK cells in 2023 Continue to anticipate cash runway into 2024
D E C E M B E R 2 0 2 2 IN V E ST O R E V E N T | SE N T I B IO SC IE N C E S Gene Circuits Can Vastly Expand the Universe of Cancer Targets and Tumors That Can Be Addressed With Cell Therapies 33 Heme Malignancies Solid Tumors N ee d f o r H ea lt h y C el l P ro te ct io n FLT3* CD33* CEA* Target GPC3* OR GATE to enhance efficacy and deepen response Multi-Arming +/- Regulator Dial to overcome immunosuppressive TME NOT GATE enables expansion to dirty targets Logic Gating Multi-Arming Gene Circuit Technologies * Senti’s current CAR-NK programs Target Target Target Target TargetTarget Target Target Target Target Target Target Target Target Target Target Target CD19 BCMA Approved autologous CAR-T cell therapies Regulator Dial
D E C E M B E R 2 0 2 2 IN V E ST O R E V E N T | SE N T I B IO SC IE N C E S Q&A 34
D E C E M B E R 2 0 2 2 | SE N T I B IO SC IE N C E S Corporate Presentation December 2022 ™
D E C E M B E R 2 0 2 2 | SE N T I B IO SC IE N C E S 2 Disclaimer Forward Looking Statements This presentation contains forward-looking statements. Statements we make in this presentation may include statements which are not historical facts and are considered forward-looking within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended, which are usually identified by the use of words such as “anticipates,” “believes,” “estimates,” “expects,” “future,” “opportunity,” “proposed,” “targets,” “intends,” “may,” “plans,” “projects,” “seeks,” “should,” “will,” and variations of such words or similar expressions. We intend these forward-looking statements to be covered by the safe harbor provisions for forward-looking statements contained in Section 27A of the Securities Act and Section 21E of the Securities Exchange Act and are making this statement for purposes of complying with those safe harbor provisions. These forward-looking statements, including statements relating to the attributes and benefits of our technology platform and our product candidates, including their therapeutic potential, our plans to submit INDs for our product candidates and the timing of such submissions, the generation and presentation of data regarding preclinical programs and the related timing, our proposed Phase 1 studies, including study design and endpoints, our ability to enter into new collaborations, our manufacturing process and its potential benefits, and our cash runway, reflect our current views about our plans, intentions, expectations, strategies and prospects, which are based on the information currently available to us and on assumptions we have made. These forward-looking statements are provided for illustrative purposes only and are not intended to serve as, and must not be relied on as a guarantee, an assurance, a prediction or a definitive statement of fact or probability. Although we believe that our plans, intentions, expectations, strategies and prospects as reflected in or suggested by those forward-looking statements are reasonable, we can give no assurance that the plans, intentions, expectations or strategies will be attained or achieved. Many actual events and circumstances are difficult or impossible to predict, are beyond our control and will differ from assumptions. Furthermore, actual results may differ materially from those described in the forward-looking statements and will be affected by a variety of risks and factors that are beyond our control including, without limitation, the risk that results observed in studies of our product candidates, including preclinical studies and future clinical trials of any of our product candidates, will not be observed in ongoing or future studies involving these product candidates, the risk that we may cease or delay clinical development of any of our product candidates for a variety of reasons (including requirements that may be imposed by regulatory authorities on the initiation or conduct of clinical trials, the amount and type of data to be generated, or otherwise to support regulatory approval, difficulties or delays in subject enrollment and continuation in current and planned clinical trials, difficulties in manufacturing or supplying our product candidates for preclinical and clinical testing, and any adverse events or other negative results that may be observed during preclinical or clinical development), our ability to obtain, maintain and protect our intellectual property, our dependence on third parties for development and manufacture of product candidates, our ability to manage expenses and to obtain additional funding when needed to support our business activities and establish and maintain strategic business alliances and new business initiatives, the impacts of macroeconomic and geopolitical events, including changing conditions from the COVID-19 pandemic, the hostilities in Ukraine, increasing rates of inflation and rising interest rates on business operations and expectation, and the risk that our product candidates may not produce therapeutic benefits or may cause other unanticipated adverse effects, as well as those set forth in the section titled “Risk Factors” in our Form 10-Q filed with the Securities and Exchange Commission (the “SEC”) on November 10, 2022, and our subsequent SEC filings. Except as required by law, we assume no obligation to update publicly any forward-looking statements, whether as a result of new information, future events or otherwise. Trademarks This document contains references to trademarks, trade names and service marks belonging to other entities. Solely for convenience, trademarks, trade names and service marks referred to in this presentation may appear without the ® or TM symbols, but such references are not intended to indicate, in any way, that the applicable owner will not assert, to the fullest extent under applicable law, its rights to these trademarks and trade names. We do not intend our use or display of other entities’ trade names, trademarks or service marks to imply a relationship with, or endorsement or sponsorship of us by, any other entities.
D E C E M B E R 2 0 2 2 | SE N T I B IO SC IE N C E S Pipeline of CAR-NK Cell Therapies Diseases: blood cancers and solid tumors Gene Circuit advantages: multi-arming, selectivity and control Manufacturing: off-the-shelf, scalable with outpatient potential Platform Collaborations Precise gene therapy for eye, CNS and liver applications Targeted and controllable iPSC cell therapies for regenerative medicine 3 Pioneering Smarter Next Generation Cell and Gene Therapies Gene Circuits Multi-Arming Logic Gating (OR and NOT GATEs) Regulator Dial Smart Sensor to reprogram cells to sense, compute, and respond to disease Founded 2016 | Public June 2022 | Anticipated Cash Runway into 2024 | Headquartered South San Francisco, CA CNS: Central Nervous System
D E C E M B E R 2 0 2 2 | SE N T I B IO SC IE N C E S 4 Industry-Leading Management With Top-Tier Board and Scientific Advisors Executive Team James Collins, PhD Scientific Co-Founder, MIT Wilson Wong, PhD Scientific Co-Founder, Boston University Ahmad (Mo) Khalil, PhD Boston University Martin Fussenegger, PhD ETH Zurich Scientific Advisors Michael Varney, PhD Erasca, Genentech Michael Kalos, PhD Arsenal, Janssen, Lilly Lawrence Fong, PhD UCSF Michael Andreeff, MD, PhD MD Anderson Cancer Center Robin Taylor, PhD, MBA SeaGen, Genentech Board of Directors David R. Epstein Former CEO of Novartis Pharma Omid Farokhzad, MD Seer Inc. Brenda Cooperstone, MD Pfizer Rare Disease James Collins, PhD Scientific Co-Founder, MIT Susan Berland Senior Financial Executive Ed Mathers NEA Tim Lu MD, PhD CEO & Co-Founder Tim Lu, MD, PhD CEO & Co-Founder Philip Lee, PhD CTO & Co-Founder Kanya Rajangam, MD, PhD Chief Medical and Development Officer (CMDO) Deb Knobelman, PhD CFO
D E C E M B E R 2 0 2 2 | SE N T I B IO SC IE N C E S CAR-NK Cell Therapy Pipeline 5
D E C E M B E R 2 0 2 2 | SE N T I B IO SC IE N C E S 6 Gene Circuits Designed to Solve for Key Cell Therapy Challenges Senti’s Gene Circuit Solutions Cancer Cell Therapy Challenges Lack of NK cell expansion and persistence Antigen escape and tumor heterogeneity Dirty targets (on-target, off-tumor toxicity) Immunosuppressive tumor microenvironment Multi-Arming Autocrine and paracrine activation with proprietary Calibrated Release IL-15 (crIL-15) and other complementary cytokines (e.g., IL-21) Bivalent activating CAR with OR Logic Gate Inhibitory CAR protects healthy cells with NOT Logic Gate Pulsed Calibrated Release IL-12 with small molecule- controlled Regulator Dial Logic Gating Logic Gating Regulator Dial
D E C E M B E R 2 0 2 2 | SE N T I B IO SC IE N C E S Extensive clinical experience with allogeneic donor-derived unengineered NK cells1 • Nearly 600 patients treated across 30+ single center academic trials • Well-tolerated o No (or minimal) CRS, neurotoxicity, GvHD • Anti-tumor activity observed in AML o 19% CR in 105 R/R AML patients aggregated from multiple trials Key limitations of unengineered NK cells Limited activity beyond AML, persistence, durability, donor variability and select single clinical center usage 7 NK Cells Compare Favorably to T Cell Based Therapies Senti’s Gene Circuit technology, donor selection and scalable manufacturing address these limitations 1 Velluchamy 2017, Bachier 2021 Capabilities Current Auto T Cells Off-the-shelf potential with broad patient accessibility Designed with Logic Gates to achieve enhanced selectivity and safety Engineered with enhanced persistence N/A ✓ ✓ ✓ Senti’s CAR-NK Cells Engineered to stimulate the patient immune system ✓
D E C E M B E R 2 0 2 2 | SE N T I B IO SC IE N C E S 0 1 2 3 4 5 0 1 2 3 4 5 6 7 8 9 Tu m o r C el l A b u n d an ce Days Vehicle Unengineered NK Cells crIL-15 CAR-NK Cells sIL-15 CAR-NK Cells 8 Calibrated Release IL-15 (crIL-15) Increases Persistence and Activation of Both CAR-NK and Immune Cells in Tumor Milieu sIL-15: secreted wild-type IL-15 0 2,000 4,000 6,000 sIL-15 CAR-NK crIL-15 CAR-NK Pa ra cr in e A ct iv it y (p ST AT 5 M FI ) Phospho STAT5 levels increased in T cells exposed to supernatant from either crIL-15 or sIL-15 CAR-NK cell culture crIL-15: IL-15 released by local proteases → autocrine and paracrine effects crIL-15 has paracrine activity and activates resting immune cells crIL-15 increases persistence of CAR- NK cells 0 0.2 0.4 0.6 0.8 1 0 5 10 15 20 25 V ia b le C el ls ( e6 ) Days in Culture crIL-15 increases CAR-NK serial killing compared to secreted IL-15 Cancer cells added Cancer cells added Cancer cells added crIL-15 CAR-NK Cells Unengineered NK Cells
D E C E M B E R 2 0 2 2 | SE N T I B IO SC IE N C E S Program Target Indications Discovery IND enabling Phase 1 Gene Circuits SENTI-202 CD33 and/or FLT3 AML, MDS and other blood cancers ✓ Multi-Arming: designed for enhanced efficacy ✓ crIL-15: autocrine and paracrine activation ✓ OR GATE: bivalent activation ✓ NOT GATE selectivity: healthy cell protection SENTI-301A GPC3 HCC and other solid tumors ✓ Multi-Arming: designed for enhanced efficacy ✓ crIL-15: autocrine and paracrine activation SENTI-401 CEA CRC and other solid tumors ✓ Multi-Arming: designed for enhanced efficacy ✓ crIL-15: autocrine and paracrine activation ✓ NOT GATE selectivity: healthy cell protection ✓ IL-21: sustained anti-tumor function Additional Programs Undisclosed Other tumors Program candidates integrate Multi-Arming, Logic Gating and/or Regulator Dial Gene Circuits 2023 IND 2024 IND 9 Senti’s Next Generation CAR-NK Cell Therapy Pipeline Tackles Hard to Treat Cancers 2H 2023 IND
D E C E M B E R 2 0 2 2 | SE N T I B IO SC IE N C E S Manufacturing 10
D E C E M B E R 2 0 2 2 | SE N T I B IO SC IE N C E S 11 Scalable Manufacturing to Support Off-The-Shelf CAR-NK Products Lentivi rus Outpatient use potential Patient Isolate from selected donors Thaw and infuse Scalable ~21 Day Process NK Cells Selected Donor Gene Circuit Engineered CAR-NK cells Engineer CryopreserveExpand Off-The-Shelf Gene Circuits 1 2 3 4 5 Easy to thaw vials Final product harvested and cryopreserved >100 doses per batch NK cells isolated from peripheral blood of selected donors NK cells efficiently engineered with Gene Circuits High post-thaw potency
D E C E M B E R 2 0 2 2 | SE N T I B IO SC IE N C E S 12 Senti Selects NK Cell Donors to Support Robust Cell Expansion Senti screens and selects GMP donors using NK cell expansion and other functional attributes to minimize variability 1.E+08 1.E+09 1.E+10 1.E+11 1.E+12 1.E+13 1.E+14 1.E+15 0 10 20 30 40 To ta l N K C el ls f ro m S el ec te d S in gl e D o n o r Culture Time (Days) Senti process can potentially generate over 100 trillion NK cells from a single donor collection Preferred Donors 0 2,000 4,000 6,000 8,000 10,000 12,000 14,000 16,000 A B C D E F G H I J K L Fo ld E xp an si o n ( 2 1 D ay s) Donors
D E C E M B E R 2 0 2 2 | SE N T I B IO SC IE N C E S 13 Senti’s Cryopreservation Process Retains High Potency of CAR-NK Products Supporting Multi-Country and Multi-Site Clinical Evaluation 0 10 20 30 40 50 60 70 80 90 100 Pre-Freeze Post-Thaw % V ia b le C el ls CAR-NK cell viability retained post-thaw in vitro Vehicle Cryopreserved CAR-NK Cells In vivo activity with cryopreserved CAR NK cells in MOLM13 AML NSG mouse model (10 days after single dose)
D E C E M B E R 2 0 2 2 | SE N T I B IO SC IE N C E S Pipeline Products 14
D E C E M B E R 2 0 2 2 | SE N T I B IO SC IE N C E S 15 SENTI-202 for CD33 and/or FLT3 Expressing Blood Cancers Multi-Armed, off-the-shelf, selective CAR-NK • OR GATE: bivalent CD33 and/or FLT3 activation → potential for deep and durable responses in acute myeloid leukemia (AML) and other blood cancers. • NOT GATE: inhibition by endomucin (EMCN) protective antigen selectively expressed on healthy hematopoietic stem cells (HSCs) → potential for improved safety and increased therapeutic window • crIL-15 → potential for increased persistence, autocrine and paracrine immune cell activation On track for IND in 2H 2023 LSCs: Leukemic Stem Cells
D E C E M B E R 2 0 2 2 | SE N T I B IO SC IE N C E S 16 SENTI-202 Has Shown Robust Preclinical Activity Across Multiple AML / MDS Models Broad in vitro killing of primary AML and MDS tumor cells In vivo suppression of tumor and increased mouse survival in MV4-11 AML NSG mouse model AML #1 0 10 20 30 40 50 60 70 80 90 100 Blasts LSCs Blasts LSCs Blasts LSCs Blasts % A M L/ M D S C el l K ill in g Unengineered NK Cells SENTI-202 CAR-NK Cells AML #2 AML #3 MDS 0 20 40 60 80 100 0 20 40 60 80 100 P ro b ab ili ty o f Su rv iv al Days Post Tumor Implantation Vehicle Unengineered NK Cells SENTI-202 CAR-NK Cells Group Vehicle Unengineered NK Cells SENTI-202 CAR-NK Cells Median Survival (Days) 49 55 81.5 Vehicle Unengineered NK Cells SENTI-202 CAR-NK Cells Day: 7 28 34
D E C E M B E R 2 0 2 2 | SE N T I B IO SC IE N C E S 17 SENTI-202 Preclinical Selectivity via Inhibitory CAR Binding Endomucin to Protect Healthy Primary Human HSCs In vitro protection of healthy primary human HSC fraction expressing EMCN In vivo protection of EMCN+ model healthy cells Endomucin was identified and validated by bioinformatics, flow cytometry, and functional assays, and is expressed on up to 76% of HSCs, but not on leukemic stem cells or blasts. FLT3 and/or CD33 expressed on tumor cells in ~95% of AML patients CD33 and/or FLT3 CAR-NK Cells SENTI-202 CAR-NK Cells Enrichment of EMCN+ cells in NSG mouse model 3 weeks after injecting 1:1 EMCN-/+ cells with CAR-NK cells 0 10 20 30 40 50 60 CD33 and/or FLT3 CAR-NK Cells SENTI-202 CAR-NK Cells % K ill in g (L eu ke m ia ) 0 5 10 15 20 25 30 35 40 45 50 CD33 and/or FLT3 CAR-NK Cells SENTI-202 CAR-NK Cells % K ill in g (E M C N + H SC s)
D E C E M B E R 2 0 2 2 | SE N T I B IO SC IE N C E S 18 Proposed Phase 1 Study in R/R CD33+ and/or FLT3+ Malignancies With Focus on AML Proposed Phase 1 study anticipated to enroll R/R CD33+ and/or FLT3+ heme malignancies • Modified “3+3” study design • Received at least 1 prior treatment including targeted agents if FLT3, IDH1/2 mutation+ • 2 of 3 patients at each dose level with AML • Disease specific expansion cohorts for AML and MDS Planned study endpoints • Safety, DLT, identify recommended Phase 2 dose • Efficacy using standard ELN 2022 criteria for AML and other disease specific consensus criteria • PK, pharmacodynamics including endomucin protection, immunogenicity Lymphodepletion Fludarabine Cyclophosphamide SENTI-202 2-3 dose levels of cells Efficacy Additional cycles+ -5 to -3 0 7 14 28Days Planned Study Treatment/ Cycle Planned data-driven seamless Phase 1 to pivotal design 1 Seer 2020; 2 Brandwein 2020 High unmet need in patients with AML • 30.5% 5-year survival1 • 5 months median overall survival at relapse2
D E C E M B E R 2 0 2 2 | SE N T I B IO SC IE N C E S 19 SENTI-301A for GPC3 Expressing Solid Tumors Multi-Armed, off-the-shelf, selective CAR-NK • GPC3 activating CAR → hepatocellular carcinoma (HCC) and other solid tumors • crIL-15 → potential for increased persistence, autocrine and paracrine immune cell activation On track for IND in 2023
D E C E M B E R 2 0 2 2 | SE N T I B IO SC IE N C E S 20 SENTI-301A Aims to Address Unmet Needs in GPC3 Expressing Solid Tumors With a Focus on HCC GPC3 is a validated cancer target • Glypican-3 (GPC3) is a membrane-bound protein normally expressed in fetal tissues such as liver and placenta. • After birth, GPC3 is not expressed in healthy liver tissue or other human organs but is overexpressed in different tumor types, notably in HCC (70-90% GPC3+)1 and other solid tumors (29-54%2 GPC3+) • Academic GPC3 CAR-T cell trials have shown promising activity but limited by CAR-T toxicities precluding multiple dosing and limited durability3 SENTI-301A is designed to target GPC3 expressing tumors • Aim to address unmet need in HCC as the initial focus given the lack of targeted therapies and lack of effective immunotherapies • Tackle multiple solid tumors with high GPC3 antigen expression via NKs multi-armed with GPC3 CAR and crIL-15 1 Zheng 2022, 2 Moek 2018, 3 Shi 2020 Squamous Cell Lung Carcinoma Hepatocellular Carcinoma Large Cell Lung Carcinoma Ovarian Clear Cell Carcinoma Differentiated Thyroid Cancer Common GPC3 expressing tumors
D E C E M B E R 2 0 2 2 | SE N T I B IO SC IE N C E S 0 1 2 3 0 1 2 3 4 5 6 Tu m o r C el l A b u n d an ce Days Vehicle Unengineered NK Cells SENTI-301A CAR-NK Cells SENTI-301A Preclinical Anti-Cancer Activity and Proposed Phase 1 Study in Advanced Solid Tumors With Focus on HCC Proposed Phase 1 study anticipated to enroll an advanced metastatic GPC3 solid tumor population • Must have received standard of care • Advanced solid tumors with focus on HCC during dose finding • Disease specific expansion cohorts of advanced HCC and other solid tumors including lung cancer Planned study treatment • Multi-dose and multi-cycle following conditioning • 2-3 cell dose levels High unmet need in patients with liver cancer 20.8% 5-year survival rate1 1 Seer 2020 (liver and intrahepatic bile duct cancer combined) Group Vehicle Unengineered NK Cells SENTI-301A CAR-NK Cells Median Survival (Days) 48 49.5 93.5 Effective in vitro serial killing of HepG2 cell line Increased survival and response in HepG2 mouse model 21 0 20 40 60 80 100 0 20 40 60 80 100 120 P ro b ab ili ty o f Su rv iv al Days Post Tumor Implantation Vehicle Unengineered NK Cells SENTI-301A Cancer cells added Cancer cells added Cancer cells added
D E C E M B E R 2 0 2 2 | SE N T I B IO SC IE N C E S 22 SENTI-401 for CEA Expressing Solid Tumors Multi-Armed, off-the-shelf, selective CAR-NK • CEACAM5 (CEA) activating CAR → colorectal cancer (CRC) and other solid tumors • NOT GATE: inhibition by VSIG2 antigen on healthy epithelial cells → potential for improved safety, increased therapeutic window and reduced on- target, off-tumor toxicity • crIL-15 → potential for increased persistence and autocrine and paracrine immune cell activation • IL-21 → construct to further potentiate persistence and efficacy of CAR-NK cells and to stimulate endogenous immune cells
D E C E M B E R 2 0 2 2 | SE N T I B IO SC IE N C E S 23 Robust Preclinical Activity With CEA CAR-NK Cells That Is Augmented by Multi- Arming With Both crIL-15 and IL-21 0 1 2 3 4 5 1 2 3 4 5 6 N o rm al iz ed T u m o r C el l A re a Days Vehicle CEA CAR-NK Cells CEA CAR-NK Cells + TGFβ crIL15 + IL21 CEA CAR-NK Cells + TGFβ Cancer cells added Cancer cells added Cancer cells added Sustained serial killing with CEA CAR-NK cells expressing crIL-15 and IL-21 in the presence of the immunosuppressive cytokine TGFb Arming CEA CARs with the combination of Senti’s proprietary crIL-15 and IL-21 results in improved anti-tumor activity of NK cells Vehicle crIL-15 CEA CAR-NK Cells crIL-15+IL21 CEA CAR-NK Cells Day: 7 28 60 Sacrificed 111 Sacrificed 0 20 40 60 80 100 0 20 40 60 80 100 120 140P ro b ab ili ty o f Su rv iv al Days Post Tumor Implantation Vehicle crIL-15 CEA CAR-NK Cells crIL-15+IL21 CEA CAR-NK Cells TGFb is an immunosuppressive tumor factor highly expressed in CRC, known to suppress immune activation and help tumor escape1 1 Nature 2018
D E C E M B E R 2 0 2 2 | SE N T I B IO SC IE N C E S Senti’s Approach to Select Paired Target and Protective Antigens Translates to Rapid Preclinical Proof of Principle for SENTI-401 Colorectal cancer CEACAM5 VSIG2 CEACAM5: 85-90% of CRC and 40-60% of other solid tumors including lung cancer1 VSIG2 was identified by bioinformatics using single cell RNA sequencing and validated as protective antigen with immunohistochemistry 1 Goldstein 2005 Healthy colon epithelium Decreased cell killing of VSIG2 expressing cells with addition of inhibitory CAR construct 0 10 20 30 40 50 60 70 80 90 CEA CAR-NK Cells CEA NOT VSIG2 CAR-NK Cells % T u m o r C el ls K ill ed CEA+ Cells CEA+ VSIG2+ Cells 24
D E C E M B E R 2 0 2 2 | SE N T I B IO SC IE N C E S 25 Senti’s Discovery Platform for Tumor-Associated Antigen and Protective Antigen to Generate Many Targets for New Logic Gated CAR-NK Candidates 52 31 Expression in tumor cells A B C 4 Healthy tissue expression of A Expression in tumor cells D E F 1 2 3 4 5 Healthy tissue expression of E RNA expression data Filter for cell surface expression Curation and experimental validation Tumor-Associated Antigen discovery Protective Antigen discovery TissuesPotential Tumor- Associated Antigens TissuesPotential Protective Antigens
D E C E M B E R 2 0 2 2 | SE N T I B IO SC IE N C E S 26 Gene Circuits Can Vastly Expand the Universe of Cancer Targets and Tumors That Can Be Addressed With Cell Therapies Heme Malignancies Solid Tumors N ee d f o r H ea lt h y C el l P ro te ct io n FLT3* CD33* CEA* Target GPC3* OR GATE to enhance efficacy and deepen response Multi-Arming +/- Regulator Dial to overcome immunosuppressive TME NOT GATE enables expansion to dirty targets Logic Gating Multi-Arming Gene Circuit Technologies * Senti’s current CAR-NK programs Target Target Target Target TargetTarget Target Target Target Target Target Target Target Target Target Target Target CD19 BCMA Approved autologous CAR-T cell therapies Regulator Dial
D E C E M B E R 2 0 2 2 | SE N T I B IO SC IE N C E S 27 Senti’s Regulator Dial Enables On-Demand Production of crIL-12 Controlled via Multiple Distinct FDA-Approved Small Molecule Oral Drugs Dose-dependent, reversible crIL-12 controlled by GRZ in vivo Vehicle GRZ at 50 mg/kg GRZ at 100 mg/kg 1 10 100 1,000 10,000 100,000 0 mg/kg50 mg/kg100 mg/kg 0 mg/kg50 mg/kg100 mg/kg 0 mg/kg50 mg/kg100 mg/kg cr IL -1 2 ( p g /m L) Day 2 (GRZ ON) Day 9 (GRZ OFF) Day 11 (GRZ ON) DrugDrug Concentration dependent crIL-12 production CAR-NK activity suppressed by M2 macrophages → Activity restored by GRZ induced crIL-12 via Regulator Dial 0 20 40 60 80 1 G ra n zy m e B ( % ) 0.1 1.0 10.0 100.0 1,000.0 10,000.0 0 0.01 0.1 1 cr IL -1 2 p g /m L GRZ (uM) - + + + Cancer target cells - - + + M2 macrophages - - - + GRZ 0.1 1.0 10.0 100.0 1000.0 0 0.1 1 10 cr IL -1 2 p g /m L Endoxifen (uM)IL-12 is a well-known immuno- stimulatory cytokine • Increases NK and T cell activation and inhibits immunosuppressive cells such as tumor-associated macrophages • Responses noted with systemic administration of IL-121 IL-12 clinical use has been limited by toxicities • Regulator Dials control IL-12 production with FDA approved oral drugs such as grazoprevir (GRZ) and endoxifen (active metabolite of tamoxifen) • Opportunities for application across multiple solid tumor indications 1 Leonard 1997
D E C E M B E R 2 0 2 2 | SE N T I B IO SC IE N C E S Platform and Collaboration Opportunities 28
D E C E M B E R 2 0 2 2 | SE N T I B IO SC IE N C E S Program Indications Gene Circuit Discovery IND enabling Phase 1 Rights Gene Therapies for Tissue-Directed Targets GC-1001/GC-1002 Eye Smart Sensor GC-1003/GC-1004 CNS Smart Sensor GC-1005 Liver Smart Sensor Cell Therapies for Regenerative Medicine GC-1101 Regenerative Medicine Regulator Dial GC-1102 Regenerative Medicine Regulator Dial GC-1103 Regenerative Medicine Smart Sensor 29 Multiple Platform Collaborations Extend Utility of Gene Circuits
D E C E M B E R 2 0 2 2 | SE N T I B IO SC IE N C E S 30 Two Collaborations to Develop Next Generation Cell and Gene Therapies AAV Gene Therapy with Cell Type-Specific Smart Sensor AAV Capsid Therapeutic Payload Low payload expression in OFF Target cell type(s) Compact promoter size to accommodate therapeutic payload transgene within ~4.5 kb AAV vector Synthetic Promoter Performance Profile: High payload expression in ON Target cell type AAV Gene Therapy with Cell Type-Specific Smart Sensor Collaboration for gene therapies Example Gene Circuits Gene Circuit-Engineered “Smart” Regenerative Medicines Senti Synthetic Promoter iPSC- derived Disease-Specific Smart Sensor1 Therapeutic Payload 2 Regulator Dial + Therapeutic Payload Oral drugOFF ON Senti’s Synthetic Promoter Collaboration for cell therapies
D E C E M B E R 2 0 2 2 | SE N T I B IO SC IE N C E S 31 Smart Sensor Promoters Are Designed to Address Key Challenges in Gene Therapy Constitutive control promoter >100% strength of CAG ~10,000-fold specificity Iterative performance optimization Sp e ci fi ci ty (r at io O N :O FF t ar ge t ce ll lin es ) Strength (fraction of CAG, an industry standard constitutive promoter) Smart Sensor Promoter Data Senti’s Gene Circuit Solutions Gene Therapy Challenges Off-target tissue toxicity Sub-optimal therapeutic performance Enhance target tissue specificity and limit off-target tissue toxicity Improve expression and increase potency Smart Sensor Smart Sensor Smart Sensor Promoters enable next-generation gene therapy by: • Enhancing specificity to target tissue(s) (and thus limiting off-target tissue toxicities) and • Increasing strength, potentially enabling more efficacious therapies
D E C E M B E R 2 0 2 2 | SE N T I B IO SC IE N C E S 32 Senti’s Gene Circuit Technology Has Broad Potential Across Modalities and Therapeutic Areas Wholly-Owned Programs with Opportunities for Future Development Opportunities for Future Development and Additional Partnering Multi-Arming Logic Gating Regulator Dial Smart Sensor Blood cancers Solid tumors Regenerative medicine Blood cancers Solid tumors Immunology Blood cancers Solid tumors Liver diseases Eye diseases CNS NK cells T cells in vivo Gene Therapy iPSCs Gene Circuit Technology
D E C E M B E R 2 0 2 2 | SE N T I B IO SC IE N C E S Program 2022 Completed Milestones 2023 Anticipated Milestones SENTI-202 CD33 and/or FLT3 AML, MDS and other blood cancers SENTI-301A GPC3 HCC and other solid tumors SENTI-401 CEA CRC and other solid tumors Present data at key scientific conferences Additional Programs Other tumors Manufacturing 33 2022 Milestones and Upcoming Value Driving Milestones Presented key preclinical data at ASH in December 2022 File IND application in 2H 2023 Presented preclinical data at SITC in November 2022 File IND application in 2023 Present dat t key scie tifi nferences Initiated research work on additional CAR-NK pipeline programs Pre-clinical PoCs for additional pipeline candidates Initiated manufacturing activities and presented data at key conferences Presented preclinical data at SITC in November 2022
D E C E M B E R 2 0 2 2 | SE N T I B IO SC IE N C E S Thank you 34