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David O'malley, MD Ovarian Cancer Targeted Approach using Biomarkers, ADC's The Next Frontier David O’Malley, M.D. Ovarian Cancer - Clinical Trial Advisor Director, Division of Gyn Oncology GOG Partners Professor, Department of OB/Gyn The Ohio State University James CCC Objectives • Understanding targeted drug therapy (ADCs) as a treatment for patients with ovarian cancer • Structure • MOA • Effective Delivery Considerations • Targets • Agents Verbal Disclosure (2 years) Consultation and/or Honorarium Institutional Research Support • Abbvie • Abbvie • Agenus • Agenus • Ambry • Amgen • Amgen • AstraZeneca • AstraZeneca • Clovis • Clovis • Immunogen • Elevar • Iovance • Immunogen • Janssen/J&J • Iovance • Merck • Janssen/J&J • Mersana • Merck • Novartis • Mersana • Novocure • Myriad Genetics • Regeneron • Novartis • Roche/Genentech • Novocure • SeaGen • Regeneron • Tesaro/GSK • Roche/Genentech • EMD Serono • SeaGen • Ergomed • Tarveda • Ajinomoto • Tesaro/GSK • GOG Foundation • Serono Inc, FDA-Approved Drugs for Ovarian Cancer 12+ Approvals since Nov 2014 More approvals in the last 6 years than the prior 60 years combined Pembrolizumab MSI/dMMR ROC (2017) Gemcitabine/Carboplatin PlSOC (2006) Olaparib Carboplatin Maintenance PlSOC (2017) (1989) Niraparib Paclitaxel Maintenance PlSOC (2017) Paclitaxel Full (1998) Accelerated (1992) Niraparib HRD ROC > 3-L (2019) 1960 1970 1980 1990 2000 2010 2020 1960 1970 1980 1990 2000 2010 2020 PLD-Full Rucaparib gBRCAmut/ Etoposide ROC (2005) sBRCAmut ROC > 2-L (2016) (1983) Melphalan Altretamine PLD-Accelerated (1964) Cisplatin Chemo + Bevacizumab (1990) ROC (1999)* (1978) PlSOC (2016) Olaparib Cyclophosphamide (1959) Topotecan Olaparib gBRCAmut 1-L ROC (1996) gBRCAmut ROC > 3-L (2014) Maintenance (2018) Bevacizumab Docetaxel Chemo + Bevacizumab (2014) PlROC (1996) 1-L + Maintenance (2018) Rucaparib Maintenance PlSOC (2018) Niraparib 1-L Maintenance (2020) Olaparib + Bev 1-L Maintenance (2020) https://www.nccn.org/professionals/physician_gls/pdf/ovarian.pdf. Accessed on 7 March 2021 The Era of Targeted Therapy in Ovarian Cancer is Here Drug Maintenance Later-line Treatment Olaparib 1 SOLO-2 (BRCA mut) Study 42 (BRCA mut) Study 19 (Dec 19, 2014) (Aug 17, 2017) SOLO-1 (BRCA mut) (Dec 19, 2018) With Bev PAOLA-1 (HRD) (May 8, 2020) 2,3 ARIEL3 Study 10 (BRCA mut) Rucaparib (April 6, 2018) ARIEL2 (BRCA mut) (Dec 19, 2016) 4 NOVA QUADRA Niraparib (Mar 27, 2017) (Oct 23, 2019) PRIMA (April 29, 2020) 5 GOG218 AURELIA Bevacizumab (June 13, 2018) (Nov 14, 2014) OCEANS – GOG213 (Dec 6, 2016) 1. Olaparib package insert. AstraZeneca Pharmaceuticals LP; 2020. 2. FDA. Summary Review for Regulatory Action: Olaparib. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206162Orig1s000SumR.pdf. Approval date December 19, 2014. Accessed April 10, 2018. 3. Rucaparib package insert. Clovis Oncology, Inc; April 2018. 4. Niraparib package insert. TESARO, Inc; August 2020. 5. https://www.drugs.com/history/avastin.html Antibody Structure • Antigen • Linker • Payload Hoffmann RM, Coumbe BGT, Josephs DH, Mele S, Ilieva KM, Cheung A, et al. Antibody structure and engineering considerations for the design and function of Antibody Drug Conjugates (ADCs). Oncoimmunology. 2018, VOL. 7, NO. 3, e1395127 Antibody Structure • Antigen Properties • High homogenous expression on tumor cells • Low/no expression on normal cells • Antigen-antibody binding is the first mechanistic step in a cascade of events • The target antigen must be well internalized by receptor mediated endocytosis • Should not be down-regulated by endocytosis or by the effects of repeated stimulation during treatment • Minimum antigen expression threshold is required for ADC efficacy Hoffmann RM, Coumbe BGT, Josephs DH, Mele S, Ilieva KM, Cheung A, et al. Antibody structure and engineering considerations for the design and function of Antibody Drug Conjugates (ADCs). Oncoimmunology. 2018, VOL. 7, NO. 3, e1395127 Antibody Structure • Payload • Drugs that are suitable for antibody conjugation and deliver an effective cytotoxic dose • The most commonly utilized payloads in ovarian cancer are: • Monomethyl auristatin E (MMAE/Vedotin) • DM4 (Ravtansine/Soravtansine) • High potency in the picomolar range is key to therapeutic benefit as payload delivery is limited by the drug to antibody ratio (DAR) • Bystander effect: membrane permeable allows for diffusion from targeted tumor cells into neighboring cells Hoffmann RM, Coumbe BGT, Josephs DH, Mele S, Ilieva KM, Cheung A, et al. Antibody structure and engineering considerations for the design and function of Antibody Drug Conjugates (ADCs). Oncoimmunology. 2018, VOL. 7, NO. 3, e1395127 Antibody Structure • Linker Properties • Forms the chemical connection between the antibody and payload • Main function is to stabilize the cytotoxic payload while in circulation and allowing release of the payload when the ADC is antigen-bound or internalized • A majority of linkers are designed to allow for payload release after internalization of the ADC • Cleavable: releases the active metabolite intracellularly after cleavage via enzymes, hydrolysis, or reduction of disulfide bonds • Non-cleavable: complete degradation of the antibody backbone before the active metabolite is releases Hoffmann RM, Coumbe BGT, Josephs DH, Mele S, Ilieva KM, Cheung A, et al. Antibody structure and engineering considerations for the design and function of Antibody Drug Conjugates (ADCs). Oncoimmunology. 2018, VOL. 7, NO. 3, e1395127 Antibody Structure • Linker Properties • Forms the chemical connection between the antibody and payload • Main function is to stabilize the cytotoxic payload while in circulation and allowing release of the payload when the ADC is antigen-bound or internalized • A majority of linkers are designed to allow for payload release after internalization of the ADC • Cleavable: releases the active metabolite intracellularly after cleavage via enzymes, hydrolysis, Choice of linker is also a key determinant of or reduction of disulfide bonds biodistribution, therapeutic activity and • Non-cleavable: complete pharmacokinetics and represents a fine degradation of the antibody backbone before the active balance between therapeutic value/toxicity metabolite is releases and distribution Hoffmann RM, Coumbe BGT, Josephs DH, Mele S, Ilieva KM, Cheung A, et al. Antibody structure and engineering considerations for the design and function of Antibody Drug Conjugates (ADCs). Oncoimmunology. 2018, VOL. 7, NO. 3, e1395127 Drug to antibody ratio (DAR) • Determined by the linker utilized and is an • Position and number of payloads bound to essential factor affecting therapeutic toxicity with the antibody can have profound effects on: an increased DAR resulting in increased toxicity. • the binding to the antigen, • While a high DAR increases the potency of the • the aggregation of the ADC, ADC, it can adversely affect pharmacokinetics • the pharmacokinetic characteristics of and distribution. the antibody construct, • Historically, the DAR has been limited to an • the safety profile of the ADC average range of 2-4 because ADCs with a • Improving the antibody site for linker higher DAR were prone to increased plasma conjugation has been greatly enhanced clearance largely due to hepatic ADC uptake. through advancements in protein engineering Hamblett KJ, Senter PD, Chace DF, Sun MM, Lenox J, Cerveny CG, et al. Effects of drug loading on the antitumor activity of a monoclonal antibody drug conjugate. Clin Cancer Res. 2004;10:7063-70. Lyon RP, Bovee TD, Doronina SO, Burke PJ, Hunter JH, Neff-LaFord HD, et al. Reducing hydrophobicity of homogeneous antibody-drug conjugates improves pharmacokinetics and therapeutic index. Nat Biotechnol. 2015;33:733-5. Sun X, Ponte JF, Yoder NC, Laleau R, Coccia J, Lanieri L, et al. Effects of Drug-Antibody Ratio on Pharmacokinetics, Biodistribution, Efficacy, and Tolerability of Antibody-Maytansinoid Conjugates. Bioconjug Chem. 2017;28:1371-81. Hamblett, K.J. Effects of Drug Loading on the Antitumor Activity of a Monoclonal Antibody Drug Conjugate. Clin. Cancer Res. 2004, 10, 7063–7070 Mechanism of Action 1. The ADC travels through the systemic circulation to the tumor tissue 2. The antibody binds to the target antigen on the cell surface 3. The ADC complex is then internalized (majority, but not all ADCs) 4. If the ADC has a cleavable linker this is cleaved releasing the cytotoxic payload intracellularly 5. If the linker is non-cleavable, lysosomal degradation of the antibody backbone occurs with release of the cytotoxic payload 6. Microtubule inhibition or other action occurs via binding of the cytotoxic payloads to tubulin (specific to cytotoxic payload utilized) 7. Cell death/apoptosis 8. Bystander Effect - Diffusion of cytotoxic payload across the cell membrane can result in cell death of neighboring cells Calo CA, O'Malley DM. Antibody-drug conjugates for the treatment of ovarian cancer. Expert Opin Biol Ther. 2020 Jun 8:1-13. doi: 10.1080/14712598.2020.1776253. Online ahead of print. PMID: 32463296 Birrer MJ, Moore KN, Betella I, Bates RC. Antibody-Drug Conjugate-Based Therapeutics: State of the Science. J Natl Cancer Inst. 2019;111:538-49. Mechanism of Action 1. The ADC travels through the systemic circulation to the tumor tissue 2. The antibody binds to the target antigen on the cell surface Calo CA, O'Malley DM. Antibody-drug conjugates for the treatment of ovarian cancer. Expert Opin Biol Ther. 2020 Jun 8:1-13. doi: 10.1080/14712598.2020.1776253. Online ahead of print. PMID: 32463296 Birrer MJ, Moore KN, Betella I, Bates RC. Antibody-Drug
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