Potent and conditional redirected T cell killing of tumor cells using Half DVD-Ig.

Philip D Bardwell; Matthew M Staron; Junjian Liu; Qingfeng Tao; Susanne Scesney; Gail Bukofzer; Luis E Rodriguez; Chee-ho Choi; Jennifer Wang; Qing Chang; Feng Dong; Cherrie Donawho; Jieyi Wang; Christine M Grinnell; Edit Tarcsa; Charles Hutchins; Tariq Ghayur; Jijie GU

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Potent and conditional redirected T cell killing of tumor cells using Half DVD-Ig.

Author: Philip D BARDWELL ¹ ; Matthew M STARON ¹ ; Junjian LIU ¹ ; Qingfeng TAO ¹ ; Susanne SCESNEY ² ; Gail BUKOFZER ³ ; Luis E RODRIGUEZ ³ ; Chee-Ho CHOI ¹ ; Jennifer WANG ¹ ; Qing CHANG ¹ ; Feng DONG ¹ ; Cherrie DONAWHO ³ ; Jieyi WANG ³ ; Christine M GRINNELL ⁴ ; Edit TARCSA ⁴ ; Charles HUTCHINS ⁵ ; Tariq GHAYUR ¹ ; Jijie GU ⁶
Author Information

1. Foundational Immunology, AbbVie Bioresearch Center, Worcester, MA, 01605, USA.
2. Global Preclinical Safety, AbbVie Bioresearch Center, Worcester, MA, 01605, USA.
3. Oncology Discovery, AbbVie Inc., North Chicago, IL, 60064, USA.
4. DMPK-BA, AbbVie Bioresearch Center, Worcester, MA, 01605, USA.
5. Research and Development, AbbVie Inc., North Chicago, IL, 60064, USA.
6. Foundational Immunology, AbbVie Bioresearch Center, Worcester, MA, 01605, USA. jijie.gu@abbvie.com.
Publication Type:Journal Article
Keywords: DVD-Ig; Half DVD-Ig; Halfbody; epidermal growth factor receptor; rCTL; redirected T-cell cytotoxicity
MeSH: Animals; Antibodies, Bispecific; immunology; Antibodies, Monoclonal; immunology; pharmacokinetics; CD3 Complex; metabolism; Cell Line, Tumor; Cytotoxicity, Immunologic; ErbB Receptors; metabolism; Female; Humans; Lymphocyte Activation; immunology; Mice, SCID; Neoplasms; immunology; pathology; Rats, Sprague-Dawley; T-Lymphocytes, Cytotoxic; immunology
From: Protein & Cell 2018;9(1):121-129
CountryChina
Language:English
Abstract: Novel biologics that redirect cytotoxic T lymphocytes (CTLs) to kill tumor cells bearing a tumor associated antigen hold great promise in the clinic. However, the ability to safely and potently target CD3 on CTL toward tumor associated antigens (TAA) expressed on tumor cells remains a challenge of both technology and biology. Herein we describe the use of a Half DVD-Ig format that can redirect CTL to kill tumor cells. Notably, Half DVD-Ig molecules that are monovalent for each specificity demonstrated reduced non-specific CTL activation and conditional CTL activation upon binding to TAA compared to intact tetravalent DVD-Ig molecules that are bivalent for each specificity, while maintaining good drug like properties and appropriate PK properties.