Slide 1: Identification of CTIM-76, a CLDN6 x CD3 bispecific antibody
December 1, 2022 Identification of CTIM-76, a CLDN6 x CD3 bispecific antibody
Slide 2: Important Notice and Disclaimers
Important Notice and Disclaimers Except for statements of historical fact, any information contained in this presentation may be a forward-looking statement that reflects the Company’s current views about future events and are subject to risks, uncertainties, assumptions and changes in circumstances
Slide 3: Overview
Overview Martin Lehr – Chief Executive Officer Claudin 6 Target Biology Eric Butz, PhD – Scientific Lead Discovery of CTIM-76 Joseph Rucker, PhD – Research Lead Concluding Remarks Martin Lehr – Chief Executive Officer Q&A Session
Slide 4: Overview
Overview Martin Lehr – Chief Executive Officer
Slide 5: Context Therapeutics Company Overview
Context Therapeutics Overview CLDN6 Candidate Selection5 Company Overview Focus on Women’s Oncology • Unmet clinical need in breast, ovarian, and endometrial cancers ONA-XR oral PR antagonist • ONA-XR is a novel, potentially first-in-class progesterone receptor (PR) antagonist • Endometrial cancer P
Slide 6: Pipeline
Pipeline 6 1 Tyligand Biosciences Ltd licensed rights to ONA-XR in China, HK, Macau * Investigator Sponsored Trial Cancer Clinical Indication Preclinical Phase 1 Clinical Phase 2 Clinical Milestones ONA-XR (PR antagonist)1 Breast Cancer 2L/3L ER+,PR+,HER2- Combination w/ elacestrant Initiated Q4 202
Slide 7: Claudin 6 Target Biology
Claudin 6 Target Biology Eric Butz, PhD – Scientific Lead
Slide 8: Claudin 6 is an Emerging Oncology Target Opportunity
Claudin 6 (CLDN6) is an Emerging Oncology Target Opportunity • CLDN6 is a tumor-specific protein that is present at high surface density across certain adult and pediatric cancers1 • CLDN6 is expressed at very low levels or absent in normal adult tissue Challenge • CLDN6 antigen is conformationally
Slide 9: Claudin (CLDN) Protein Family
Claudin (CLDN) Protein Family • Tight junctions (TJ) regulate cell barrier and permeability • CLDN proteins constitute a structural core of TJ, along with junction adhesion molecule (JAM) and occludin • 27 CLDN proteins have been characterized to date • Dysregulation of CLDN protein expression and f
Slide 10: Many CLDN Proteins are Associated with Disease
Many CLDN Proteins are Associated with Disease CLDN6 Target Biology CLDN6 Candidate Selection10 CLDN Disease CLDN 1 Colitis, skin permeability CLDN 2 Colorectal cancer, IBD CLDN 3 Psoriasis, ovarian cancer CLDN 4 Diabetes, ovarian cancer CLDN 5 Cerebral edema, depression CLDN 6 Multiple cancers CLDN
Slide 11: The Challenge: developing a highly selective CLDN6 antibody
The Challenge: developing a highly selective CLDN6 antibody CLDN6 Target Biology CLDN6 Candidate Selection11 CLDN9 CLDN6 CLDN4 CLDN3 CLDN5 CLDN8 CLDN17 CLDN2 CLDN14 CLDN20 CLDN7 CLDN1 CLDN19 CLDN34 CLDN12 CLDN23 CLDN16 CLDN24 CLDN22 CLDN25 CLDN18 CLDN11 CLDN15 CLDN10 • CLDN6 antigen is conformationa
Slide 12: CLDN6 is an Oncofetal Protein
CLDN6 is an Oncofetal Protein, Considered Favorable Candidates for Immunotherapy CLDN6 Target Biology CLDN6 Candidate Selection12 • Normally present at higher levels during embryonic development • Turned off or have low levels of expression in adult tissues • Increased expression of these antigens c
Slide 13: CLDN6 is Selectively Expressed on Cancer Cells
CLDN6 is Selectively Expressed on Cancer Cells CLDN6 Target Biology CLDN6 Candidate Selection13 (a) adrenal gland, (b) fallopian tube, (c) kidney, (d) liver, (e) thyroid, (f) prostate, (g) esophagus, (h) stomach, (i) colon, (j) cerebrum, (k) cerebellum, (l) spinal cord. (m) thymus, (n) spleen, (o) b
Slide 14: CLDN6 Exhibits High, Homogeneous Expression on Cancer Cells
CLDN6 Exhibits High, Homogeneous Expression on Cancer Cells • CLDN6 protein expression in testicular and ovarian tumors each from eight different patients analyzed by IHC • Testicular: all embryonal carcinoma • Ovarian: (a) adenocarcinoma, (b,c,e-h) serous cystadenocarcinoma, (d) papillary serous cy
Slide 15: CLDN6 Has the Potential to Reach a Large Patient Population
CLDN6 Has the Potential to Reach a Large Patient Population ~62,500 patients per year in the US only in Relapse/Refractory Setting CLDN6 Target Biology 15 Selected Cancer indications Incidence R/R Incidence CLDN6 Positive Patient Population Based on R/R Incidence Testicular 9,910 400 95%1 380 Ovaria
Slide 16: Key Developments in CLDN6 R&D Timeline
Key Developments in CLDN6 R&D Timeline R&D activity has recently accelerated CLDN6 Target Biology CLDN6 Candidate Selection16 1 https://www.clinicaltrialsregister.eu/ctr-search/trial/2013-002755-15/results 2 Hamilton et al, AACR, Virtual: 2020 April 2022 BNT211 (BioNTech) Clinical Proof of Concept f
Slide 17: CLDN6 – Drug Development Strategy Comparison
CLDN6 – Drug Development Strategy Comparison CLDN6 is a tumor-associated antigen (TAA) for tumor-targeting therapeutics such as CAR-T and T cell engaging bispecific antibodies CLDN6 Target Biology CLDN6 Candidate Selection17 Drug Development Strategy CLDN6 Dependence / Rationale Supporting Evidence
Slide 18: CLDN6 is Not Ideally Suited for Conventional mAb or ADC Therapy
CLDN6 is Not Ideally Suited for Conventional mAb or ADC Therapy CLDN6 has weak signaling activity and poor internalization • CLDN6 and CLDN18.2 antibodies from Integral Molecular were converted to ADC utilizing MMAE payload • ADC constructs evaluated in OVCAR3 cell killing assay • CLDN6 ADC cell kil
Slide 19: CLDN6 is an Ideal Tumor Associated Antigen for T-cell Targeting
CLDN6 is an Ideal Tumor Associated Antigen for T-cell Targeting BNT211 (BioNTech) demonstrates preliminary clinical proof of concept CLDN6 Target Biology CLDN6 Candidate Selection19 • CARVac intended to drive in vivo expansion, persistence, and efficacy of CAR-T • Strategy intended to minimize numbe
Slide 20: BNT211 ± CARVac Exhibited Activity Across CLDN6+ Advanced Cancers
BNT211 ± CARVac Exhibited Activity Across CLDN6+ Advanced Cancers Initial clinical efficacy benchmarked to standard of care or emerging treatments CLDN6 Target Biology CLDN6 Candidate Selection20 Testicular: Haanen 2022, Oechsle 2011, Adra 2018, Necchi 2016 Ovarian: Haanen 2022, Matulonis 2022, Puja
Slide 21: Limitations of CLDN6 CAR-T + CARVac Approach
Limitations of CLDN6 CAR-T + CARVac Approach CLDN6 Target Biology CLDN6 Candidate Selection21 Target Asset Ph 1 Dose Range RP2D CLDN6 BNT211 1x10 7 to 1x10 9 cells TBD CLDN18.2 CT041 2.5x10 8 to 5x10 8 cells 2.5 x 10 8 cells • BNT211 + CARVac T-cell infusion is consistent with similar CAR-T products
Slide 22: CTIM-76 Differentiation
BNT211 + CARVac CTIM-76 Complex + In-Patient Hospital administered autologous cell therapy in combination with repeat mRNA vaccination utilizing lipid nanoparticle carrier Easy + Out-Patient Outpatient infusion every 2-4 weeks based on IgG backbone Required None Weak T cell persistence Fully stimula
Slide 23: Discovery of CTIM-76
Discovery of CTIM-76 Joseph Rucker, PhD – Research Lead
Slide 24: Bispecific Antibody Considerations
• Multiple formats evaluated Bispecific Antibody Considerations Candidates evaluated based on a range of scaffolds, CLDN6, and T-cell engagers Discovery of CTIM-76 CLDN6 Candidate Selection24 NHP = non-human primate • High affinity anti-CLDN6 binding • High specificity for CLDN6 vs other CLDN − Espe
Slide 25: CTIM-76 Nominated as Development Candidate
CTIM-76 Nominated as Development Candidate Wide therapeutic window • Highly selective CLDN6 binding Fab arm • CD3 binding single-chain Fv domain is designed to be functionally monovalent to avoid aberrant T-cell activation, potentially enhancing safety profile • Silenced Fc domain to avoid T-cell ac
Slide 26: Identification of CLDN6-targeting Arm
Identification of CLDN6-targeting Arm The Problem • The extracellular binding region of CLDN6 is highly conserved with CLDN3 (78% homology), CLDN4 (81%), and CLDN9 (96%) • Antigen is conformationally dependent, which limits conventional antibody discovery methods • Human CLDNs share approximately 95
Slide 27: Identification of Selective CLDN6 MAbs
Identification of Selective CLDN6 MAbs Discovery of CTIM-76 CLDN6 Candidate Selection27 • IM301 (CLDN6 arm of CTIM-76) exhibits high CLDN6 selectivity1 • Epitope mapping of IM301 identifies unique binding location relative to benchmark IMAB027/ASP150 (Ganymed/Astellas) IM171 -10 -9 -8 -7 -6 0 50,000
Slide 28: CTIM-76 Exhibits Excellent Selectivity and Specificity
CTIM-76 Exhibits Excellent Selectivity and Specificity Discovery of CTIM-76 CLDN6 Candidate Selection28 • IM301 Mab screened for specificity using Integral Molecular Membrane Proteome Array, consisting of ~6,000 human membrane proteins in their native state in unfixed cells • IM301 Mab was cross-rea
Slide 29: Specific Lysis: T-cell mediated cell killing is dependent on CLDN6 expression
Specific Lysis T-cell mediated cell killing is dependent on CLDN6 expression Discovery of CTIM-76 CLDN6 Candidate Selection29 K562-CLDN6 OV90 HEK CLDN6 Expression High Medium Low CTIM-76 (EC50) 0.0004 nM 0.049 nM 2.79 nM OV90 Cell LineK562-CLDN6 Cell Line HEK Cell Line -4 -3 -2 -1 0 0 50 100 Log [bs
Slide 30: CTIM-76 Preferentially Targets CLDN6 Over Other Claudin Family Proteins
CTIM-76 Preferentially Targets CLDN6 Over Other Claudin Family Proteins Discovery of CTIM-76 CLDN6 Candidate Selection30 • There is high sequence homology between CLDN6 and CLDN9 in the extracellular loops • CTIM-76 preferentially targets CLDN6, with minimal activity against CLDN9-expressing cells •
Slide 31: CTIM-76 has the Potential for a Wide Therapeutic Window
Discovery of CTIM-76 CLDN6 Candidate Selection31 CTIM-76 has the Potential for a Wide Therapeutic Window • Cytokine production evaluated in exogenous (CLDN6-K562) cell line model • Cytokine production happens well above the concentration of maximal killing (EC50 = 0.0004 nM) in CLDN6-K562 cells at 4
Slide 32: CTIM-76 Exhibits Ideal Immunomodulatory Properties
Discovery of CTIM-76 CLDN6 Candidate Selection32 CTIM-76 Exhibits Ideal Immunomodulatory Properties • Exogenous (CLDN6-K562) results replicated in endogenous (OV90) cell line model • Cytokine production happens well above the concentration of maximal killing (EC50 = 0.049 nM) in OV90 cells at 48 hou
Slide 33: Role of Bispecific Format in Activity
Role of Bispecific Format in Activity CTIM-76 format demonstrates superior potency compared to a traditional BiTE molecule Discovery of CTIM-76 CLDN6 Candidate Selection33 -4 -3 -2 -1 0 -50 0 50 100 Log [bsAb] (nM) % S p e c if ic C y to to x ic it y Negative Control IMC-2-7 CTIM-76 IMC-2-7 Tandem s
Slide 34: Concluding Remarks
Concluding Remarks Martin Lehr – Chief Executive Officer
Slide 35: CLDN6 is an Exciting Cancer Target Within the T-cell Directed Therapy Landscape
CLDN6 is an Exciting Cancer Target Within the T-cell Directed Therapy Landscape1 Concluding Remarks CLDN6 Candidate Selection35 Large Addressable Patient Population Small Addressable Patient Population Validated Target Emerging Target PRAME MAGE-A4 CLDN6 CLDN18.2 NY-ESO-1 MSLN gp100 CD19 COL6A3 AFP
Slide 36: Competitive Landscape
Competitive Landscape1 Concluding Remarks CLDN6 Candidate Selection36 Candidate IND Phase 1 ADC Bispecific Antibody Cell Therapy CAR-NK CAR-NK + IL7 secreting vector BNT211 CAR-T + CARVac TJ-46CB 2+2 bsAb CLDN6x4IBB UCLA-23-ADC CLDN6 + MMAE AMG794 BiTE CLDN6xCD3 BNT142 mRNA encoded BsAb CLDN6xCD3 Un
Slide 37: Clinical Experience for CLDN6 Therapies is Nascent
Clinical Experience for CLDN6 Therapies is Nascent Company Program Description / Details3 Active Programs BioNTech BNT211: CLDN6CAR-T + CARVac (Phase 1) Initial data for BNT211 was presented April 2022 (AACR), with an update in Sept 2022 (ESMO). Received PRIME Designation for testicular cancer June
Slide 38: Select Early-stage Bispecific Antibody Transactions in 2022
Select Early-stage Bispecific Antibody Transactions in 20221 Concluding Remarks CLDN6 Candidate Selection38 Licensee Licensor Target Asset Stage Geography Upfront ($M) Milestones ($M) TeneoTwo AstraZeneca CD19 TNB-486 Phase 1 WW $100 $1,165 Macrogenics Gilead CD123 MGD024 IND WW $60 $1,700 LAVA Seag
Slide 39: Next Steps and Summary
Next Steps and Summary Concluding Remarks CLDN6 Candidate Selection39 Encouraging efficacy signals • CLDN6-selective activity across binding and cytotoxicity Well tolerated • Preferential cytotoxicity over activation of free circulating cytokines • PK consistent with IgG backbone • No significant sa
Slide 40: Q&A Session
MARTIN LEHR Chief Executive Officer Q&A Session ERIC BUTZ, PhD Scientific Lead JOSEPH RUCKER, PhD Research Lead JENNIFER MINAI Chief Financial Officer
Slide 41: Advancing Medicines for Female Cancers
ADVANCING MEDICINES FOR FEMALE CANCERS © CONTEXT THERAPEUTICS 2022