Novel Enediyne-Based Antibody-Drug Conjugates for Cancers

University Of Florida, Gainesville FL

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Abstract

PROJECT SUMMARY The 15 FDA-approved antibody-drug conjugates (ADCs) and nearly all ADCs in clinical trials are prepared by random drug conjugation, affording a heterogeneous ADC mixture that compromises both efficacy and safety. Site-specific conjugation is a major recent improvement to ADC development, yielding homogeneous ADCs with improved therapeutic index. Drugs currently used as ADC payloads generally fall into three categories – tubulin binders, DNA-targeting, and topoisomerase inhibitors. The ADC field is in critical need of diversifying payloads to address challenges encountered with the current ADCs. We propose in this application to develop tiancimycin (TNM)- and lactimidomycin (LTM)-based and site-specifically conjugated ADCs, targeting CD79b and ROR1, as next generation therapies for hematologic malignancies. Our hypotheses are: (i) TNMs and LTMs are outstanding ADC payloads owing to their exquisite potency and modes of action (MOAs), (ii) TNM and LTM biosynthesis and fermentation optimization enable the production of designer payload candidates to develop the linker chemistry, (iii) the dual variable domain (DVD) platform enables site-specific conjugation of TNMs and LTMs to the orthogonally reactive Lys or arginine (Arg) residue of DVDs to generate homogeneous ADCs, and (iv) complementary targeting of CD79b and ROR1 helps evaluate the novel TNM-, LTM-, or TNM-LTM dual drug-based ADCs and develop them into next-generation ADCs for hematologic malignances that currently lack effective treatments. The specific aims for this renewal project period are: development and optimization of linker and conjugation chemistry and preparation (i) of TNM- and LTM-based and CD79b- and ROR1-targeting ADCs by site-specific conjugation to the reactive Lys residue of DVDs and (ii) of TNM-LTM dual drug-based and CD79b- and ROR1-targeting ADCs by site-specific conjugation to the orthogonally active Lys and Arg residues of DVDs, and evaluation of selectivity and potency (iii) of TNM-, LTM- , and TNM-LTM dual drug-based and CD79b- and ROR1-targeting ADCs against selected CD79b+ and/or ROR1+ cell lines and primary patient samples and (iv) of LTM- and TNM-LTM dual drug-based and CD79b- and ROR1-targeting ADCs against selected CD79b+ and/or ROR1+ cell lines or primary patient samples, in combination with drugs known to induce resistance, first in vitro and subsequently in vivo in mouse models. The outcomes of this application include: (i) fundamental contributions to ADCs and (ii) a panel of TNM-, LTM- , and TNM-LTM dual drug-based and CD79b- and ROR1-targeting ADCs as next-generation therapies for hematologic malignances. The long-term goal of our research is to discover novel microbial natural products and harness their exquisite cytotoxicity and MOAs as ADC payloads for anticancer drug discovery.