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

AI Article Synopsis

  • A novel bispecific antibody targeting GUCY2C and CD3ε has been developed for treating solid tumors, showcasing effective T-cell retargeting capabilities.* -
  • The antibody was humanized and optimized using various methods like structure-guided mutagenesis and phage display to enhance stability and reduce potential manufacturing issues.* -
  • The optimized antibody demonstrated strong efficacy in laboratory models and favorable pharmacokinetics in cynomolgus monkeys, with ongoing clinical trials for further evaluation.*

Article 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 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 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833764PMC
http://dx.doi.org/10.1080/19420862.2020.1850395DOI Listing

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