Slide 1: Targeting HER2 with Immune-Stimulating Antibody Conjugates (ISACs)
Targeting HER2 with Immune-Stimulating Antibody Conjugates (ISACs) David Dornan, Ph.D. Bolt Biotherapeutics, Inc., Redwood City, California, USA
Slide 2: Disclosure Information
Disclosure Information David Dornan I have the following financial relationships to disclose: Stockholder in: Bolt Biotherapeutics, Inc. Employee of: Bolt Biotherapeutics, Inc. Consultant for: Teon Therapeutics, Inc. I will discuss investigational use in my presentation: BDC-1001 in Advanced HER2-Ex
Slide 3: Tumor Microenvironment and Antigen Presenting Cells
Tumor Microenvironment and Antigen Presenting Cells Immunosuppressive Tumor Microenvironment ▪ Various cells in the TME (Tregs, MDSCs, M2s, CAFs etc.) limit a robust anti- tumor immune response by producing immunosuppressive cytokines such as: TME-mediated ▪ PGE2 – suppresses M1 cytokine secretion a
Slide 4: Pattern Recognition Receptors Play Key Roles in the Activation of the Innate Immune Response
Pattern Recognition Receptors Play Key Roles in the Activation of the Innate Immune Response • PRR agonists (e.g., TLR7/8/9, STING, and NLRP3) create an immune microenvironment poised for an anti-tumor immune response • Enhanced antigen presentation for T cell-mediated killing • Reducing function of
Slide 5: Dual TLR7 & TLR8 Agonism Optimizes for Productive Anti-tumor Immune Response
Dual TLR7 & TLR8 Agonism Optimizes for Productive Anti-tumor Immune Response • TLR7 agonism activates pDCs, TLR7 and/or TLR8 agonism activate cDCs • IFNa contributes to activation/maturation cDCs and CD8 survival • Activated cDCs and pDCs produce cytokines and chemokines to convert “cold” to “warm”
Slide 6: Boltbody ISAC Mechanism of Action
Boltbody ISAC Mechanism of Action
Slide 7: ISACs Require Tumor Antigen Recognition, FcR engagement, and TLR Agonism
ISACs Require Tumor Antigen Recognition, FcR engagement, and TLR Agonism HCC1954, 5 mg/kg, q5d x 6
Slide 8: BDC-1001 Surrogate Enhances Secretion of Cytokines, Chemokines, and Recruitment of Myeloid Cells in the TME
BDC-1001 Surrogate Enhances Secretion of Cytokines, Chemokines, and Recruitment of Myeloid Cells in the TME Trastuzumab BDC-1001 Surrogate Isotype Isotype ISAC Trastuzumab BDC-1001 Surrogate HCC1954, 5 mg/kg, 24 hours post-Tx HCC1954, 9 days post-Tx
Slide 9: BDC-1001 Surrogate Efficacy Requirements
BDC-1001 Surrogate Efficacy Requirements 5 mg/kg (~80% HER2 RO) BDC-1001 Surrogate + Clodronate 1 mg/kg (~60% HER2 RO) + Control Liposomes 0.2 mg/kg (~20% HER2 RO) Trastuzumab Day Post Treatment Day Post Treatment Requirement for ~60% HER2 RO Requirement for Phagocytes HCC1954, Tx 5 mg/kg, q5d x 6 H
Slide 10: Tumor Elimination in Large, Immunologically Cold & Well-Established Tumors
Tumor Elimination in Large, Immunologically Cold & Well-Established Tumors BDC-1001 Surrogate Isotype ISAC rHER2 mAb MMC syngeneic, Tx 5 mg/kg, q5d x2
Slide 11: BDC-1001 Surrogate Enhances Secretion of Cytokines, Chemokines, as well as Recruitment of Myeloid and CD8 Cells in TME
BDC-1001 Surrogate Enhances Secretion of Cytokines, Chemokines, as well as Recruitment of Myeloid and CD8 Cells in TME BDC-1001 rHER2 Surrogate mAb Isotype Isotype ISAC rHER2 mAb BDC-1001 Surrogate MMC syngeneic, Tx 5 mg/kg MMC syngeneic, 6 days post-Tx
Slide 12: Requirement for Phagocytes and CD8 T cells for Maximal ISAC Efficacy
Requirement for Phagocytes and CD8 T cells for Maximal ISAC Efficacy MMC syngeneic, Tx 5 mg/kg, q5d x 2
Slide 13: BDC-1001 Surrogate MMC Mice that are Cured by Tx are Resistant to Rechallenge
BDC-1001 Surrogate MMC Mice that are Cured by Tx are Resistant to Rechallenge Previously cured mice Previously cured mice with rHER2 T785-ISAC with rHER2 T785-ISAC Tumor naïve Tumor naïve BDC-1001 surrogate-treated mice that experienced complete tumor regression for >90 d after their last treatment
Slide 14: BDC-1001 – Ongoing Phase 1/2 Schema in Advance HER2-Expressing Solid Tumors
BDC-1001 – Ongoing Phase 1/2 Schema in Advance HER2-Expressing Solid Tumors ClinicalTrials.gov Identifier: NCT04278144 Phase1/2 Monotherapy Trial Schema: Parts 1 and 3 HER2 eligibility based on cohort Safety, PK, Efficacy, PD Biomarkers HER2+ Breast Cancer 16+14 Dose Expansion 8 mg/kg N=3 Eligibilit
Slide 15: Generating Proof of Mechanism for the ISAC Approach
Generating Proof of Mechanism for the ISAC Approach BDC-1001 Trastuzumab (anti-HER2) biosimilar conjugated to proprietary TLR7/8 agonist via a non-cleavable linker Preclinical Proof of Mechanism: Trastuzumab • “Three-Factor Authentication” for localized immune response and safety (anti-HER2) • Engag