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Improving Antibody‐Tubulysin Conjugates through Linker Chemistry and Site‐Specific Conjugation
Author(s) -
Hamilton Joseph Z.,
Pires Thomas A.,
Mitchell Jamie A.,
Cochran Julia H.,
Emmerton Kim K.,
Zaval Margo,
Stone Ivan J.,
Anderson Martha E.,
Jin Steven,
Waight Andrew B.,
Lyon Robert P.,
Senter Peter D.,
Jeffrey Scott C.,
Burke Patrick J.
Publication year - 2021
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202000889
Subject(s) - linker , conjugate , chemistry , in vivo , potency , pharmacology , combinatorial chemistry , stereochemistry , immunoconjugate , drug delivery , biochemistry , in vitro , antibody , monoclonal antibody , biology , immunology , organic chemistry , mathematical analysis , mathematics , microbiology and biotechnology , computer science , operating system
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 multidrug‐resistant cell lines differentiates 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.