Slide 1: Discovery of First-in-Class Precision Antibody Drug Conjugates Targeting Mutant Calreticulin
Discovery of First-in-Class Precision Antibody Drug Conjugates Targeting Mutant Calreticulin For the Treatment of Myeloproliferative Neoplasms. Norman Fultang1, Ashley Schwab1, Sharayu Chandratre1, Ian Johnson1, Jake Karwoski1, Neha Bhagwat1, Arpita Mondal1, Min Wang1, Yue Zou1, Andrew Buesking1, Ma
Slide 2: Disclosures and Financial Relationships
Disclosures and Financial Relationships Disclaimer The opinions expressed in this presentation and on the following slides are solely those of the presenter and not necessarily those of Prelude Therapeutics Incorporated. As the information contained in this presentation are based on public informati
Slide 3: Mutated Calreticulin (mutCALR) Represents a Promising ADC Target in MPNs
Mutated Calreticulin (mutCALR) Represents a Promising ADC Target and Pathway to Potential Molecular Remission in MPNs ➢ Mutant CALR is a neoantigen presented on the cell surface of malignant cells but not normal cells and is found in 25-35% of patients with MF and ET ➢ Current therapies for MPNs pro
Slide 4: SWI/SNF ATPases SMARCA2 and SMARCA4 are Key Therapeutic Targets in MPN
SWI/SNF ATPases SMARCA2 and SMARCA4 are Key Therapeutic Targets in MPN ➢ SWI/SNF nucleosome remodeling complexes regulate chromatin accessibility and are essential for SMARCA2/4 hematopoietic stem cell maintenance. 1 Dual Degrader ➢ Deregulated SWI/SNF activity has been linked to the pathogenesis of
Slide 5: Prelude's SMARCA2/4 Degrader Payloads Demonstrate Robust Efficacy in MPN Preclinical Models
Prelude’s SMARCA2/4 Degrader Payloads Demonstrate Robust Efficacy in MPN Preclinical Models With Limited Tolerability Robust Inhibition of tumor growth and splenomegaly ➢ SMARCA2/4 dual degraders demonstrate OCI-AML3, AML Ba/F3-MPL-CALRins5 % Reduction of Splenomegaly robust efficacy including regre
Slide 6: Precision ADCs (pADCs) Represent the Next Generation of ADCs
Precision ADCs (or “pADCs”) Represent the Next Generation of ADCs Current ADCs Precision ADCs Toxicity & Cross Resistance Therapeutic Index Cytotoxic Targeted Chemotherapy Degrader Payloads Efficacy • Non-selective Genotoxic Payloads • Dual Targeting with Precision ADCs • Limited Payload Diversity •
Slide 7: Identification of an Internalizing CALR Antibody for Selective Delivery of Degraders
Identification of an Internalizing CALR Antibody To Enable Selective Delivery of SMARCA2/4 Degraders to CALR Mutant Cells CALR antibody preferentially binds mutant CALR Ba/F3 cells over WT Ba/F3 CALRins5 Ba/F3 CALRWT ➢ Non-antagonizing, internalizing CALR antibody Antibody binding (GMFI) 1500 Isotyp
Slide 8: CALR pADCs Demonstrate Robust and Selective SMARCA2/4 Degradation and Cytotoxicity
CALR pADCs Demonstrate Robust and Selective SMARCA2/4 Degradation and Cytotoxicity in CALR Mutant Cells Degradation Assay, 48h Anti-proliferation Assay 7 days Ba/F3 CALRins5 Ba/F3 CALRWT SMARCA2/4 CALR pADC Degrader 0 .05 0.5 1 10 0 .05 0.5 1 10 µg/mL Cell viability (%) 100 SMARCA2 SMARCA4 50 >68x T
Slide 9: Presence of Soluble Mutant CALR Protein Does Not Affect CALR pADC Cytotoxicity
Presence of Soluble Mutant CALR Protein Does Not Affect CALR pADC Cytotoxicity TF-1 anti-proliferation, 7 days • CALRdel52 Mutant CALR is secreted by mutant cells CALRWT Supplemented Recombinant and detected in MPN patient plasma CALRdel52 % Cell Viability 100 (mean: 25.6 ng/mL; range: 0–160 ng/mL).
Slide 10: CALR pADCs Demonstrate Robust Anti-Tumor Activity In Vivo and Are Well-Tolerated
CALR pADCs Demonstrate Robust Anti-Tumor Activity In Vivo and Are Well-Tolerated Robust tumor growth inhibition 2000 Vehicle CALR x SMARCA ✓ CALR x SMARCA pADCs drive robust inhibition of growth in a TF-1 Tumor Volume 1500 TF-1 CALRdel52 Vehicle or (mm3) SEM pADC 5e6 cells ADC Treatment i.v. 1000
Slide 11: CALR pADCs Selectively Target and Eliminate Diseased CALR Mutant Cells from MPN Primary Cultures
CALR pADCs Selectively Target and Eliminate Diseased CALR Mutant Cells from MPN Primary Cultures Liquid Culture Growth Assay MF (CALRins5) PBMCs, Day 7 Myelofibrosis PBMCs mCALR+ cells mCALR- healthy cells 7 days RPMI + Cytokines Vehicle 0.1 µg/mL CALR pADC 1 µg/ml CALR pADC CALR pADC Selective kill
Slide 12: Summary: Prelude's CALR pADCs
Summary: Prelude’s CALR pADCs: A Selective and Efficacious Approach for Targeting CALR-Mutant Disease ✓ Prelude’s CALR pADCs selectively degrade SMARCA2/4 in CALR mutant cells and robustly inhibit CALR-mutant cell growth in vitro and in vivo ✓ In MPN models, CALR pADCs target and eliminate diseased
Slide 13: Acknowledging the Prelude Research Team
Acknowledging the Prelude Research Team Screening, Preclinical Biology, and DMPK Ashley Schwab Kirsten Gallagher Min Wang Sharayu Chandratre Yue Zou Sandy Geeganage Jake Karwoski Arpita Mondal Sang Hyun Lee Ian Johnson Joe Rager Diane Heiser Prelude headquarters Neha Bhagwat Nick Stahl Wan-Jen Hong