Anti-CD20/CD3 T cell-dependent bispecific antibody for the treatment of B cell malignancies

• Published in: Science translational medicine 2015-05, Vol.7 (287), p.287ra70-287ra70
• Main Authors: Sun, Liping L, Ellerman, Diego, Mathieu, Mary, Hristopoulos, Maria, Chen, Xiaocheng, Li, Yijin, Yan, Xiaojie, Clark, Robyn, Reyes, Arthur, Stefanich, Eric, Mai, Elaine, Young, Judy, Johnson, Clarissa, Huseni, Mahrukh, Wang, Xinhua, Chen, Yvonne, Wang, Peiyin, Wang, Hong, Dybdal, Noel, Chu, Yu-Waye, Chiorazzi, Nicholas, Scheer, Justin M, Junttila, Teemu, Totpal, Klara, Dennis, Mark S, Ebens, Allen J
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Bispecific - immunology; Antibodies, Bispecific - pharmacokinetics; Antibodies, Bispecific - therapeutic use; Antigens, CD20 - immunology; CD3 Complex - immunology; Humans; Leukemia, B-Cell - immunology; Leukemia, B-Cell - therapy; Macaca fascicularis; Mice; Mice, Transgenic; T-Lymphocytes - immunology
• ISSN: 1946-6234; 1946-6242
• DOI: 10.1126/scitranslmed.aaa4802

Bispecific antibodies and antibody fragments in various formats have been explored as a means to recruit cytolytic T cells to kill tumor cells. Encouraging clinical data have been reported with molecules such as the anti-CD19/CD3 bispecific T cell engager (BiTE) blinatumomab. However, the clinical use of many reported T cell-recruiting bispecific modalities is limited by liabilities including unfavorable pharmacokinetics, potential immunogenicity, and manufacturing challenges. We describe a B cell-targeting anti-CD20/CD3 T cell-dependent bispecific antibody (CD20-TDB), which is a full-length, humanized immunoglobulin G1 molecule with near-native antibody architecture constructed using "knobs-into-holes" technology. CD20-TDB is highly active in killing CD20-expressing B cells, including primary patient leukemia and lymphoma cells both in vitro and in vivo. In cynomolgus monkeys, CD20-TDB potently depletes B cells in peripheral blood and lymphoid tissues at a single dose of 1 mg/kg while demonstrating pharmacokinetic properties similar to those of conventional monoclonal antibodies. CD20-TDB also exhibits activity in vitro and in vivo in the presence of competing CD20-targeting antibodies. These data provide rationale for the clinical testing of CD20-TDB for the treatment of CD20-expressing B cell malignancies.