Slide 1: Discovery of First-in-Class Calreticulin-targeted Degrader Antibody Conjugates Delivering a CDK9 Degrader Payload
Discovery of First-in-Class Calreticulin-targeted Degrader Antibody Conjugates Delivering a CDK9 Degrader Payload for the Treatment of CALR-mutated MPNs Norman Fultang1, Ashley Schwab1, Sharayu Chandratre1, Jake Karwoski1, Grace Davis1, Ian Johnson1, Neha Bhagwat1, Yue Zou1, Arpita Mondal1, Max Foro
Slide 2: Mutated Calreticulin Represents a Promising ADC Target in MPNs
Mutated Calreticulin (mCALR) Represents a Promising ADC Target and Pathway to Potential Molecular Remission in Myeloproliferative Neoplasms (MPNs) ➢ Mutant CALR is a neoantigen presented on the surface of malignant cells but not normal cells and is found in 25-35% of patients with MF and ET ➢ Curren
Slide 3: CDK9 is a Key Vulnerability in MPNs
CDK9 is a Key Vulnerability in MPNs ➢ Aberrant activity of master transcription elongation factor, CDK9, contributes to malignant myeloproliferation in several myeloid neoplasms MYC MCL1 including AML, MDS and MPN. 1,2 ➢ CALR mutant MPNs exhibit transcriptional addiction making them vulnerable to CD
Slide 4: CDK9 Degrader Payload Demonstrates Robust Efficacy in MPN Preclinical Models, Albeit With Limited Tolerability
Prelude’s CDK9 Degrader Payload (Unconjugated) Demonstrates Robust Efficacy in MPN Preclinical Models, Albeit With Limited Tolerability Robust regression of tumor growth and splenomegaly SET-2 (JAK2V617F) Ba/F3-MPL-CALRins5 ➢ Prelude’s CDK9 degrader achieves complete tumor regressions in JAK/STAT- T
Slide 5: Degrader Antibody Conjugates Represent The Next Generation of ADCs
Degrader Antibody Conjugates (DACs) Represent The Next Generation of ADCs Current ADCs DACs Reduced Toxicity and Resistance Improved Therapeutic Index Cytotoxic Targeted Improved Efficacy Chemotherapy Degrader Payloads • Non-selective genotoxic payloads ✓ Dual targeting expands therapeutic index • R
Slide 6: mAb Selectively Binds and Internalizes in CALR Mutant Cells But not WT
mCALR mAb Selectively Binds and Internalizes in CALR Mutant Cells But not WT mCALR mAb selectively binds and internalizes in mutCALR cells but not WT Antibody Binding Antibody Internalization Ba/F3-TpoR Ba/F3-TpoR Internalization Signal CALRins5 ➢ mCALR mAb selectively binds and is 100 500000 Antibo
Slide 7: Robust and Selective CDK9 Degradation and Cytotoxicity in mCALR Cells
mCALR x CDK9d DACs Demonstrate Robust and Selective CDK9 Degradation and Cytotoxicity in mCALR Cells Selective CDK9 Degradation mCALR x CDK9d DAC TF-1 CALRdel52 TF-1 CALRins5 TF-1 CALRWT “mutCALR x CDK9-degrader Degrader Antibody Conjugate” DAC, µg/mL CDK9 GAPDH PRT-CDK9 107x DC50 selectivity Mutant
Slide 8: Selectively Inhibit the Proliferation of mCALR Progenitors
mCALR x CDK9d DACs Selectively Inhibit the Proliferation of mCALR Progenitors MF/ET or Healthy BMMCs CD34+ isolation Healthy HSCs MF Type II ET Type I ET Type II ET Type I CALR WT CALRins5 CALRdel52 CALRins5 CALRdel52 % HSPCs (CD34+ Lin-) 100 Vehicle or 14 days mCALR DAC * * Media + cytokines *** or
Slide 9: Selectively Inhibit Mutant Megakaryopoiesis While Sparing Normal Megakaryopoiesis
mCALR x CDK9d DACs Selectively Inhibit Mutant Megakaryopoiesis While Sparing Normal Megakaryopoiesis Diseased megakaryocyte differentiation in mCALR HSCs Normal megakaryocyte differentiation in healthy HSCs Healthy or Myelofibrosis CD34+ HSCs CALRins5 Myelofibrosis CD34+ CD41+ Megakaryocytes 100 mCA
Slide 10: Inhibit mCALR Tumor Growth In Vivo and Are Well-Tolerated
mCALR x CDK9d DACs Inhibit mCALR Tumor Growth In Vivo and Are Well-Tolerated Robust tumor growth inhibition Well tolerated ➢ mCALR × CDK9d DACs significantly inhibit TF-1 CALRdel52 xenograft 2000 TF-1 CALRdel52 xenograft growth in vivo 20 Vehicle Body weight change (%) Vehicle mCALR x 10 mCALR x CDK
Slide 11: Summary: Prelude's mCALR DACs Represent a First-in-Class, Selective and Efficacious New Modality
Summary: Prelude’s mCALR DACs Represent a First-in-Class, Selective and Efficacious New Modality for Targeting CALR-Mutant Disease ✓ mCALR x CDK9d DAC delivers a CDK9 degrader selectively to the malignant clone ✓ Deep mutant-selective killing across cell lines, HSPCs, and primary cultures, highlight