Improving Antibody-Tubulysin Conjugates Through Linker Chemistry and Site-Specific Conjugation.

Improving Antibody-Tubulysin Conjugates Through Linker Chemistry and Site-Specific Conjugation.
ChemMedChem. 2020 Dec 24;:
Authors: Hamilton JZ, Pires TA, Mitchell JA, Cochran JH, Emmerton KK, Zaval M, Stone IJ, Anderson ME, Jin S, Waight AB, Lyon RP, Senter PD, Jeffrey SC, Burke PJ
Abstract
Tubulysins have emerged in recent years as a compelling drug class for delivery to tumor cells via antibodies. The ability of this drug class to exert bystander activity while retaining potency against multi-drug resistant cell lines differentiate them from other microtubule disrupting agents. Tubulysin M, a synthetic analogue, has proven to be active and well-tolerated as an antibody-drug conjugate (ADC) payload, but has the liability of being susceptible to acetate hydrolysis at the C11 position, leading to attenuated potency. In this work, we examine the ability of the drug-linker and conjugation site to preserve acetate stability. Our findings show that in contrast to a more conventional protease-cleavable dipeptide linker, the β-glucuronidase-cleavable glucuronide linker protects against acetate hydrolysis and improves ADC activity in vivo. In addition, site-specific conjugation can positively impact both acetate stability and in vivo activity. Together, these findings provide the basis for a highly optimized delivery strategy for tubulysin M.
PMID: 33369163 [PubMed - as supplied by publisher]

Source: ChemMedChem - December 24, 2020 Category: Chemistry Authors: Hamilton JZ, Pires TA, Mitchell JA, Cochran JH, Emmerton KK, Zaval M, Stone IJ, Anderson ME, Jin S, Waight AB, Lyon RP, Senter PD, Jeffrey SC, Burke PJ Tags: ChemMedChem Source Type: research