Discovery and optimization of a novel anti-GUCY2c x CD3 bispecific antibody for the treatment of solid tumors.

Autor: Root AR; BioMedicine Design, Pfizer Inc ., Cambridge, MA, USA., Guntas G; BioMedicine Design, Pfizer Inc ., Cambridge, MA, USA., Katragadda M; BioMedicine Design, Pfizer Inc ., Cambridge, MA, USA., Apgar JR; BioMedicine Design, Pfizer Inc ., Cambridge, MA, USA., Narula J; BioMedicine Design, Pfizer Inc ., Cambridge, MA, USA., Chang CS; BioMedicine Design, Pfizer Inc ., Cambridge, MA, USA., Hanscom S; BioMedicine Design, Pfizer Inc ., Cambridge, MA, USA., McKenna M; BioMedicine Design, Pfizer Inc ., Cambridge, MA, USA., Wade J; BioMedicine Design, Pfizer Inc ., Cambridge, MA, USA., Meade C; BioMedicine Design, Pfizer Inc ., Cambridge, MA, USA., Ma W; BioMedicine Design, Pfizer Inc ., Cambridge, MA, USA., Guo Y; BioMedicine Design, Pfizer Inc ., Cambridge, MA, USA., Liu Y; BioMedicine Design, Pfizer Inc ., Cambridge, MA, USA., Duan W; BioMedicine Design, Pfizer Inc ., Cambridge, MA, USA., Hendershot C; BioMedicine Design, Pfizer Inc ., Cambridge, MA, USA., King AC; BioMedicine Design, Pfizer Inc ., Cambridge, MA, USA., Zhang Y; BioMedicine Design, Pfizer Inc ., Cambridge, MA, USA., Sousa E; BioMedicine Design, Pfizer Inc ., Cambridge, MA, USA., Tam A; BioMedicine Design, Pfizer Inc ., Cambridge, MA, USA., Benard S; BioMedicine Design, Pfizer Inc ., Cambridge, MA, USA., Yang H; BioMedicine Design, Pfizer Inc ., Cambridge, MA, USA., Kelleher K; BioMedicine Design, Pfizer Inc ., Cambridge, MA, USA., Jin F; BioMedicine Design, Pfizer Inc ., Cambridge, MA, USA., Piche-Nicholas N; BioMedicine Design, Pfizer Inc ., Cambridge, MA, USA., Keating SE; BioMedicine Design, Pfizer Inc ., Dublin, IE, USA., Narciandi F; BioMedicine Design, Pfizer Inc ., Dublin, IE, USA., Lawrence-Henderson R; BioMedicine Design, Pfizer Inc ., Andover, MA, USA., Arai M; BioMedicine Design, Pfizer Inc ., Cambridge, MA, USA., Stochaj WR; BioMedicine Design, Pfizer Inc ., Cambridge, MA, USA., Svenson K; BioMedicine Design, Pfizer Inc ., Cambridge, MA, USA., Mosyak L; BioMedicine Design, Pfizer Inc ., Cambridge, MA, USA., Lam K; BioMedicine Design, Pfizer Inc ., Andover, MA, USA., Francis C; BioMedicine Design, Pfizer Inc ., Andover, MA, USA., Marquette K; BioMedicine Design, Pfizer Inc ., Cambridge, MA, USA., Wroblewska L; BioMedicine Design, Pfizer Inc ., Cambridge, MA, USA., Zhu HL; BioMedicine Design, Pfizer Inc ., Andover, MA, USA., Sheehan AD; BioMedicine Design, Pfizer Inc ., Dublin, IE, USA., LaVallie ER; BioMedicine Design, Pfizer Inc ., Cambridge, MA, USA., D'Antona AM; BioMedicine Design, Pfizer Inc ., Cambridge, MA, USA., Betts A; BioMedicine Design, Pfizer Inc ., Cambridge, MA, USA., King L; BioMedicine Design, Pfizer Inc ., Andover, MA, USA., Rosfjord E; Oncology Research & Development, Pfizer Inc ., Pearl River, NY, USA., Cunningham O; BioMedicine Design, Pfizer Inc ., Dublin, IE, USA., Lin L; BioMedicine Design, Pfizer Inc ., Cambridge, MA, USA., Sapra P; Oncology Research & Development, Pfizer Inc ., Pearl River, NY, USA., Tchistiakova L; BioMedicine Design, Pfizer Inc ., Cambridge, MA, USA., Mathur D; Oncology Research & Development, Pfizer Inc ., Pearl River, NY, USA., Bloom L; BioMedicine Design, Pfizer Inc ., Cambridge, MA, USA.
Jazyk: angličtina
Zdroj: MAbs [MAbs] 2021 Jan-Dec; Vol. 13 (1), pp. 1850395.
DOI: 10.1080/19420862.2020.1850395
Abstrakt: 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.
Databáze: MEDLINE