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Binding Activities and Antitumor Properties of a New Mouse/Human Chimeric Antibody Specific for GD2 Ganglioside Antigen

Authors' Affiliations: ¹ Inserm, Université de Nantes, Nantes Atlantique Universités U601, Département de Recherche en Cancérologie, 9 quai Moncousu, F-44093 Nantes, France; and ² Université de Nantes, Inserm, Nantes Atlantique Universités, U601, Faculté de Pharmacie, 1 Rue Gaston Veil, F-44035 Nantes, France.

Requests for reprints: Stéphane Birklé, Centre de Recherche en Cancérologie, UMR U601 INSERM, 9 quai Moncousu, F44093 Nantes, France. Phone: 33-240-084747; Fax: 33-240-356997; E-mail: Stephane.Birkle{at}univ-nantes.fr.

Purpose: We previously generated a mouse monoclonal antibody (mAb) specific for the tumor-associated GD2 ganglioside antigen. Here, we describe the development of a chimeric anti-GD2 mAb for more effective tumor immunotherapy.

Experimental Design: We cloned the cDNA encoding the immunoglobulin light and heavy chains of the 60C3 anti-GD2 mAb, and constructed chimeric genes by linking the cDNA fragments of the variable regions of the murine light and heavy chains to cDNA fragments of the human and 1 constant regions, respectively.

Results: The resultant chimeric anti-GD2 mAb, c.60C3, showed identical binding affinity and specificity to that of its murine counterpart. Both c.60C3 and 60C3 were rapidly internalized by tumor cells at 37°C. When human serum and human natural killer cells were used as effectors in complement-mediated cytotoxicity and antibody-dependent cell cytotoxicity, respectively, c.60C3 was more effective in killing GD2-expressing tumor cells. However, c.60C3 was ineffective at inducing cell death by apoptosis, although binding of 60C3 induced apoptotic death in vitro. In an in vivo, GD2-expressing, syngeneic tumor model, i.v. injection of c.60C3, but not of 60C3, significantly suppressed tumor growth in mice (P < 0.0005).

Conclusion: Immune effector functions mediated by this antibody and its potentially reduced immunogenicity make chimeric c.60C3 a promising therapeutic agent against neuroectodermic tumors.