A new class of bispecific antibodies to redirect T cells for cancer immunotherapy.

Abstract

Various constructs of bispecific antibodies (bsAbs) to redirect effector T cells for the targeted killing of tumor cells have shown considerable promise in both preclinical and clinical studies. The single-chain variable fragment (scFv)-based formats, including bispecific T-cell engager (BiTE) and dual-affinity re-targeting (DART), which provide monovalent binding to both CD3 on T cells and to the target antigen on tumor cells, can exhibit rapid blood clearance and neurological toxicity due to their small size (~55 kDa). Herein, we describe the generation, by the modular DOCK-AND-LOCK™) (DNL™) method, of novel T-cell redirecting bispecific antibodies, each comprising a monovalent anti-CD3 scFv covalently conjugated to a stabilized dimer of different anti-tumor Fabs. The potential advantages of this design include bivalent binding to tumor cells, a larger size (~130 kDa) to preclude renal clearance and penetration of the blood-brain barrier, and potent T-cell mediated cytotoxicity. These prototypes were purified to near homogeneity, and representative constructs were shown to provoke the formation of immunological synapses between T cells and their target tumor cells in vitro, resulting in T-cell activation and proliferation, as well as potent T-cell mediated anti-tumor activity. In addition, in vivo studies in NOD/SCID mice bearing Raji Burkitt lymphoma or Capan-1 pancreatic carcinoma indicated statistically significant inhibition of tumor growth compared with untreated controls.

• Authors: Diane L Rossi, Edmund A Rossi, Thomas M Cardillo, David M Goldenberg, Chien-Hsing Chang
• Journal: mAbs (MAbs) 2014 Mar-Apr Vol. 6 Issue 2 Pg. 381-91 ISSN: 1942-0870 [Electronic] United States
• PMID: 24492297 (Publication Type: Journal Article)

Chemical References

• Antigens, Neoplasm
• CD3 Complex
• Cancer Vaccines
• Epitopes
• Immunoglobulin Fab Fragments
• Single-Chain Antibodies

Topics

• Animals
• Antigens, Neoplasm (immunology, metabolism)
• Burkitt Lymphoma (immunology, therapy)
• CD3 Complex (metabolism)
• Cancer Vaccines
• Cell Proliferation (drug effects)
• Cytotoxicity, Immunologic (drug effects)
• Epitopes (genetics)
• Humans
• Immunoglobulin Fab Fragments (genetics, metabolism)
• Immunological Synapses (drug effects)
• Immunotherapy (methods)
• Jurkat Cells
• Lymphocyte Activation (drug effects)
• Mice
• Mice, SCID
• Pancreatic Neoplasms (immunology, therapy)
• Protein Binding
• Protein Engineering
• Single-Chain Antibodies (genetics, metabolism)
• T-Lymphocytes (immunology, transplantation)
• Xenograft Model Antitumor Assays