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Discovery and optimization of a novel anti-GUCY2c x CD3 bispecific antibody for the treatment of solid tumors.
- Source :
-
MAbs [MAbs] 2021 Jan-Dec; Vol. 13 (1), pp. 1850395. - Publication Year :
- 2021
-
Abstract
- We report here the discovery and optimization of a novel T cell retargeting anti-GUCY2C x anti-CD3ε bispecific antibody for the treatment of solid tumors. Using a combination of hybridoma, phage display and rational design protein engineering, we have developed a fully humanized and manufacturable CD3 bispecific antibody that demonstrates favorable pharmacokinetic properties and potent in vivo efficacy. Anti-GUCY2C and anti-CD3ε antibodies derived from mouse hybridomas were first humanized into well-behaved human variable region frameworks with full retention of binding and T-cell mediated cytotoxic activity. To address potential manufacturability concerns, multiple approaches were taken in parallel to optimize and de-risk the two antibody variable regions. These approaches included structure-guided rational mutagenesis and phage display-based optimization, focusing on improving stability, reducing polyreactivity and self-association potential, removing chemical liabilities and proteolytic cleavage sites, and de-risking immunogenicity. Employing rapid library construction methods as well as automated phage display and high-throughput protein production workflows enabled efficient generation of an optimized bispecific antibody with desirable manufacturability properties, high stability, and low nonspecific binding. Proteolytic cleavage and deamidation in complementarity-determining regions were also successfully addressed. Collectively, these improvements translated to a molecule with potent single-agent in vivo efficacy in a tumor cell line adoptive transfer model and a cynomolgus monkey pharmacokinetic profile (half-life>4.5 days) suitable for clinical development. Clinical evaluation of PF-07062119 is ongoing.
- Subjects :
- Animals
Antibodies, Bispecific pharmacokinetics
Antibodies, Bispecific therapeutic use
Cell Line, Tumor
Female
Humans
Hybridomas
Macaca fascicularis immunology
Macaca fascicularis metabolism
Mice, Inbred BALB C
Neoplasms immunology
Neoplasms metabolism
Protein Engineering methods
Single-Chain Antibodies immunology
Single-Chain Antibodies pharmacokinetics
Single-Chain Antibodies therapeutic use
T-Lymphocytes immunology
T-Lymphocytes metabolism
Mice
Antibodies, Bispecific immunology
CD3 Complex immunology
Immunotherapy, Adoptive methods
Neoplasms therapy
Receptors, Enterotoxin immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1942-0870
- Volume :
- 13
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- MAbs
- Publication Type :
- Academic Journal
- Accession number :
- 33459147
- Full Text :
- https://doi.org/10.1080/19420862.2020.1850395