Affordable Access

deepdyve-link
Publisher Website

Site-Specific Antibody-Drug Conjugates in Triple Variable Domain Fab Format.

Authors
  • Hwang, Dobeen1
  • Rader, Christoph1
  • 1 Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL 33458, USA.
Type
Published Article
Journal
Biomolecules
Publisher
MDPI AG
Publication Date
May 14, 2020
Volume
10
Issue
5
Identifiers
DOI: 10.3390/biom10050764
PMID: 32422893
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

The interest in replacing the conventional immunoglobulin G (IgG) format of monoclonal antibodies (mAbs) and antibody-drug conjugates (ADCs) with alternative antibody and antibody-like scaffolds reflects a need to expand their therapeutic utility and potency while retaining their exquisite specificity, affinity, and low intrinsic toxicity. For example, in the therapy of solid malignancies, the limited tumor tissue penetration and distribution of ADCs in IgG format mitigates a uniform distribution of the cytotoxic payload. Here, we report triple variable domain Fab (TVD-Fab) as a new format that affords the site-specific and stable generation of monovalent ADCs without the Fc domain and a drug-to-antibody ratio (DAR) of 2. TVD-Fabs harbor three variable fragment (Fv) domains: one for tumor targeting and two for the fast, efficient, precise, and stable conjugation of two cargos via uniquely reactive lysine residues. The biochemical and in vitro cytotoxicity properties of a HER2-targeting TVD-Fab before and after conjugation to a tubulin inhibitor were validated. In vivo, the TVD-Fab antibody carrier revealed a circulatory half-life of 13.3 ± 2.5 h and deeper tumor tissue distribution compared to our previously reported dual variable domain (DVD)-IgG1 format. Taken together, the TVD-Fab format merits further investigations as an antibody carrier of site-specific ADCs targeting solid malignancies.

Report this publication

Statistics

Seen <100 times