Discovery and optimization of a novel anti-GUCY2c x CD3 bispecific antibody for the treatment of solid tumors
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 C...
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| Format: | Article |
| Language: | English |
| Published: |
Taylor & Francis Group
2021-01-01
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| Series: | mAbs |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/19420862.2020.1850395 |
| _version_ | 1811343678504960000 |
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| author | Adam R. Root Gurkan Guntas Madan Katragadda James R. Apgar Jatin Narula Chew Shun Chang Sara Hanscom Matthew McKenna Jason Wade Caryl Meade Weijun Ma Yongjing Guo Yan Liu Weili Duan Claire Hendershot Amy C. King Yan Zhang Eric Sousa Amy Tam Susan Benard Han Yang Kerry Kelleher Fang Jin Nicole Piche-Nicholas Sinead E. Keating Fernando Narciandi Rosemary Lawrence-Henderson Maya Arai Wayne R. Stochaj Kristine Svenson Lidia Mosyak Khetemcnee Lam Christopher Francis Kimberly Marquette Liliana Wroblewska H. Lily Zhu Alfredo Darmanin Sheehan Edward R. LaVallie Aaron M. D’Antona Alison Betts Lindsay King Edward Rosfjord Orla Cunningham Laura Lin Puja Sapra Lioudmila Tchistiakova Divya Mathur Laird Bloom |
| author_facet | Adam R. Root Gurkan Guntas Madan Katragadda James R. Apgar Jatin Narula Chew Shun Chang Sara Hanscom Matthew McKenna Jason Wade Caryl Meade Weijun Ma Yongjing Guo Yan Liu Weili Duan Claire Hendershot Amy C. King Yan Zhang Eric Sousa Amy Tam Susan Benard Han Yang Kerry Kelleher Fang Jin Nicole Piche-Nicholas Sinead E. Keating Fernando Narciandi Rosemary Lawrence-Henderson Maya Arai Wayne R. Stochaj Kristine Svenson Lidia Mosyak Khetemcnee Lam Christopher Francis Kimberly Marquette Liliana Wroblewska H. Lily Zhu Alfredo Darmanin Sheehan Edward R. LaVallie Aaron M. D’Antona Alison Betts Lindsay King Edward Rosfjord Orla Cunningham Laura Lin Puja Sapra Lioudmila Tchistiakova Divya Mathur Laird Bloom |
| author_sort | Adam R. Root |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-13T19:33:05Z |
| format | Article |
| id | doaj.art-25a52ae4f12b462d933f760c7786789d |
| institution | Directory Open Access Journal |
| issn | 1942-0862 1942-0870 |
| language | English |
| last_indexed | 2024-04-13T19:33:05Z |
| publishDate | 2021-01-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | mAbs |
| spelling | doaj.art-25a52ae4f12b462d933f760c7786789d2022-12-22T02:33:07ZengTaylor & Francis GroupmAbs1942-08621942-08702021-01-0113110.1080/19420862.2020.1850395Discovery and optimization of a novel anti-GUCY2c x CD3 bispecific antibody for the treatment of solid tumorsAdam R. Root0Gurkan Guntas1Madan Katragadda2James R. Apgar3Jatin Narula4Chew Shun Chang5Sara Hanscom6Matthew McKenna7Jason Wade8Caryl Meade9Weijun Ma10Yongjing Guo11Yan Liu12Weili Duan13Claire Hendershot14Amy C. King15Yan Zhang16Eric Sousa17Amy Tam18Susan Benard19Han Yang20Kerry Kelleher21Fang Jin22Nicole Piche-Nicholas23Sinead E. Keating24Fernando Narciandi25Rosemary Lawrence-Henderson26Maya Arai27Wayne R. Stochaj28Kristine Svenson29Lidia Mosyak30Khetemcnee Lam31Christopher Francis32Kimberly Marquette33Liliana Wroblewska34H. Lily Zhu35Alfredo Darmanin Sheehan36Edward R. LaVallie37Aaron M. D’Antona38Alison Betts39Lindsay King40Edward Rosfjord41Orla Cunningham42Laura Lin43Puja Sapra44Lioudmila Tchistiakova45Divya Mathur46Laird Bloom47BioMedicine Design, Pfizer Inc., Cambridge, MA, USABioMedicine Design, Pfizer Inc., Cambridge, MA, USABioMedicine Design, Pfizer Inc., Cambridge, MA, USABioMedicine Design, Pfizer Inc., Cambridge, MA, USABioMedicine Design, Pfizer Inc., Cambridge, MA, USABioMedicine Design, Pfizer Inc., Cambridge, MA, USABioMedicine Design, Pfizer Inc., Cambridge, MA, USABioMedicine Design, Pfizer Inc., Cambridge, MA, USABioMedicine Design, Pfizer Inc., Cambridge, MA, USABioMedicine Design, Pfizer Inc., Cambridge, MA, USABioMedicine Design, Pfizer Inc., Cambridge, MA, USABioMedicine Design, Pfizer Inc., Cambridge, MA, USABioMedicine Design, Pfizer Inc., Cambridge, MA, USABioMedicine Design, Pfizer Inc., Cambridge, MA, USABioMedicine Design, Pfizer Inc., Cambridge, MA, USABioMedicine Design, Pfizer Inc., Cambridge, MA, USABioMedicine Design, Pfizer Inc., Cambridge, MA, USABioMedicine Design, Pfizer Inc., Cambridge, MA, USABioMedicine Design, Pfizer Inc., Cambridge, MA, USABioMedicine Design, Pfizer Inc., Cambridge, MA, USABioMedicine Design, Pfizer Inc., Cambridge, MA, USABioMedicine Design, Pfizer Inc., Cambridge, MA, USABioMedicine Design, Pfizer Inc., Cambridge, MA, USABioMedicine Design, Pfizer Inc., Cambridge, MA, USABioMedicine Design, Pfizer Inc., Dublin, IE, USABioMedicine Design, Pfizer Inc., Dublin, IE, USABioMedicine Design, Pfizer Inc., Andover, MA, USABioMedicine Design, Pfizer Inc., Cambridge, MA, USABioMedicine Design, Pfizer Inc., Cambridge, MA, USABioMedicine Design, Pfizer Inc., Cambridge, MA, USABioMedicine Design, Pfizer Inc., Cambridge, MA, USABioMedicine Design, Pfizer Inc., Andover, MA, USABioMedicine Design, Pfizer Inc., Andover, MA, USABioMedicine Design, Pfizer Inc., Cambridge, MA, USABioMedicine Design, Pfizer Inc., Cambridge, MA, USABioMedicine Design, Pfizer Inc., Andover, MA, USABioMedicine Design, Pfizer Inc., Dublin, IE, USABioMedicine Design, Pfizer Inc., Cambridge, MA, USABioMedicine Design, Pfizer Inc., Cambridge, MA, USABioMedicine Design, Pfizer Inc., Cambridge, MA, USABioMedicine Design, Pfizer Inc., Andover, MA, USAOncology Research & Development, Pfizer Inc., Pearl River, NY, USABioMedicine Design, Pfizer Inc., Dublin, IE, USABioMedicine Design, Pfizer Inc., Cambridge, MA, USAOncology Research & Development, Pfizer Inc., Pearl River, NY, USABioMedicine Design, Pfizer Inc., Cambridge, MA, USAOncology Research & Development, Pfizer Inc., Pearl River, NY, USABioMedicine Design, Pfizer Inc., Cambridge, MA, USAWe 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.https://www.tandfonline.com/doi/10.1080/19420862.2020.1850395T cell bispecificT cell retargetingT-BsAbimmuno-oncologyGUCY2CGuanlyate cyclase 2c (GCC) |
| spellingShingle | Adam R. Root Gurkan Guntas Madan Katragadda James R. Apgar Jatin Narula Chew Shun Chang Sara Hanscom Matthew McKenna Jason Wade Caryl Meade Weijun Ma Yongjing Guo Yan Liu Weili Duan Claire Hendershot Amy C. King Yan Zhang Eric Sousa Amy Tam Susan Benard Han Yang Kerry Kelleher Fang Jin Nicole Piche-Nicholas Sinead E. Keating Fernando Narciandi Rosemary Lawrence-Henderson Maya Arai Wayne R. Stochaj Kristine Svenson Lidia Mosyak Khetemcnee Lam Christopher Francis Kimberly Marquette Liliana Wroblewska H. Lily Zhu Alfredo Darmanin Sheehan Edward R. LaVallie Aaron M. D’Antona Alison Betts Lindsay King Edward Rosfjord Orla Cunningham Laura Lin Puja Sapra Lioudmila Tchistiakova Divya Mathur Laird Bloom Discovery and optimization of a novel anti-GUCY2c x CD3 bispecific antibody for the treatment of solid tumors mAbs T cell bispecific T cell retargeting T-BsAb immuno-oncology GUCY2C Guanlyate cyclase 2c (GCC) |
| title | Discovery and optimization of a novel anti-GUCY2c x CD3 bispecific antibody for the treatment of solid tumors |
| title_full | Discovery and optimization of a novel anti-GUCY2c x CD3 bispecific antibody for the treatment of solid tumors |
| title_fullStr | Discovery and optimization of a novel anti-GUCY2c x CD3 bispecific antibody for the treatment of solid tumors |
| title_full_unstemmed | Discovery and optimization of a novel anti-GUCY2c x CD3 bispecific antibody for the treatment of solid tumors |
| title_short | Discovery and optimization of a novel anti-GUCY2c x CD3 bispecific antibody for the treatment of solid tumors |
| title_sort | discovery and optimization of a novel anti gucy2c x cd3 bispecific antibody for the treatment of solid tumors |
| topic | T cell bispecific T cell retargeting T-BsAb immuno-oncology GUCY2C Guanlyate cyclase 2c (GCC) |
| url | https://www.tandfonline.com/doi/10.1080/19420862.2020.1850395 |
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