A new class of bispecific antibodies to redirect T cells for cancer immunotherapy.
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.
Immunomedics, Inc; Morris Plains, NJ USA.
Diane L
DL
Rossi
Immunomedics, Inc; Morris Plains, NJ USA; IBC Pharmaceuticals, Inc; Morris Plains, NJ USA.
Edmund A
EA
Rossi
Immunomedics, Inc; Morris Plains, NJ USA.
Thomas M
TM
Cardillo
Immunomedics, Inc; Morris Plains, NJ USA; IBC Pharmaceuticals, Inc; Morris Plains, NJ USA; Garden State Cancer Center; Center for Molecular Medicine and Immunology; Morris Plains, NJ USA.
David M
DM
Goldenberg
Immunomedics, Inc; Morris Plains, NJ USA; IBC Pharmaceuticals, Inc; Morris Plains, NJ USA.
Chien-Hsing
CH
Chang
D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology / Q000378:metabolism; D002051:Burkitt Lymphoma / Q000276:immunology / Q000628:therapy*; D017252:CD3 Complex / Q000378:metabolism; D019496:Cancer Vaccines; D049109:Cell Proliferation / Q000187:drug effects; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D000939:Epitopes / Q000235:genetics; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000235:genetics / Q000378:metabolism; D054992:Immunological Synapses / Q000187:drug effects; D007167:Immunotherapy / Q000379:methods*; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D016513:Mice, SCID; D010190:Pancreatic Neoplasms / Q000276:immunology / Q000628:therapy*; D011485:Protein Binding; D015202:Protein Engineering; D057127:Single-Chain Antibodies / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D023041:Xenograft Model Antitumor Assays
D000951:Antigens, Neoplasm; D017252:CD3 Complex; D019496:Cancer Vaccines; D000939:Epitopes; D007140:Immunoglobulin Fab Fragments; D057127:Single-Chain Antibodies
Burkitt lymphoma; DOCK-AND-LOCK; T-cell redirected therapy; bispecific antibody; pancreatic cancer