The Impact of Conjugation Mode and Site on Tubulysin Antibody‐Drug‐Conjugate Efficacy and Stability

The Impact of Conjugation Mode and Site on Tubulysin Antibody‐Drug‐Conjugate Efficacy and Stability

Antibody‐drug conjugates (ADCs) represent a prominent class of biotherapeutics engineered to selectively deliver cytotoxic payloads to tumors, thereby facilitating targeted cell killing. While first‐generation ADCs, created by conjugating payloads to surface‐accessible lysine or hinge‐cysteine resid...

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Main Authors: Sayumi Yamazoe, Qinqin Cheng, Srikanth Kotapati, Vangipuram S. Rangan, Mei‐Chen Sung, Madhura Deshpande, Aarti Jashnani, Cong Qiang, Michael J. Smith, Chin Pan, Gavin Dollinger, Arvind Rajpal, Pavel Strop, Chetana Rao
Format: Article
Language:English
Published: Wiley-VCH 2025-08-01
Series:ChemistryOpen
Subjects:
antibody‐drug conjugates
deconjugation
payload metabolism
site‐specific conjugations
tubulysin
Online Access:https://doi.org/10.1002/open.202400522
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Summary:Antibody‐drug conjugates (ADCs) represent a prominent class of biotherapeutics engineered to selectively deliver cytotoxic payloads to tumors, thereby facilitating targeted cell killing. While first‐generation ADCs, created by conjugating payloads to surface‐accessible lysine or hinge‐cysteine residues, have achieved clinical success, several site‐specific ADCs with defined drug‐to‐antibody ratios are currently under clinical investigation. Herein, the efficacy, stability, and pharmacokinetics of ADCs generated by attaching the drug linker to surface‐exposed lysine residues, hinge‐cysteine residues, and the C’E loop in the CH2 domain (mediated by bacterial transglutaminase) using a tubulysin payload are compared. In N87 xenograft mice, the order of efficacy is C’E loop > hinge‐cysteine > lysine‐conjugated ADCs. Among the three ADCs evaluated, the site‐specific ADC demonstrates superior in vivo stability (minimal payload‐linker deconjugation and limited payload metabolism/deacetylation) and favorable pharmacokinetics (longer half‐life, low clearance, high exposure). In contrast, the lysine‐conjugated ADC exhibits the least stability and poorest pharmacokinetics, which directly correlate with its efficacy. Further investigation into cysteine‐engineered site‐specific ADCs with payloads conjugated at various sites confirms that both the conjugation chemistry and the site of conjugation significantly influence the in vivo stability and pharmacokinetics of site‐specific ADCs.
ISSN:2191-1363

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