Binding activities and antitumor properties of a new mouse/human chimeric antibody specific for GD2 ganglioside antigen.
OBJECTIVE
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.


METHODS
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 kappa and gamma1 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 degrees 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).


CONCLUSIONS
Immune effector functions mediated by this antibody and its potentially reduced immunogenicity make chimeric c.60C3 a promising therapeutic agent against neuroectodermic tumors.
Alvarez-Rueda
Nidia
N
Inserm, Université de Nantes, Nantes Atlantique Universités U601, Département de Recherche en Cancérologie, 9 quai Moncousu, F-44093 Nantes, France.
Leprieur
Stéphanie
S
Clémenceau
Béatrice
B
Supiot
Stéphane
S
Sébille-Rivain
Véronique
V
Faivre-Chauvet
Alain
A
Davodeau
François
F
Paris
François
F
Barbet
Jacques
J
Aubry
Jacques
J
Birklé
Stéphane
S
D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D000920:Antibody-Dependent Cell Cytotoxicity; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000276:immunology; D003165:Complement System Proteins / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D018076:DNA, Complementary / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005678:G(M2) Ganglioside / Q000276:immunology*; D015870:Gene Expression / Q000235:genetics; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics / Q000276:immunology; D007147:Immunoglobulin Light Chains / Q000235:genetics / Q000276:immunology; D007075:Immunoglobulin M / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D007142:Immunoglobulin gamma-Chains / Q000235:genetics / Q000276:immunology; D007145:Immunoglobulin kappa-Chains / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000494:pharmacology*; D015996:Survival Rate; D014162:Transfection; D014183:Transplantation, Heterologous
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D018076:DNA, Complementary; D007143:Immunoglobulin Heavy Chains; D007147:Immunoglobulin Light Chains; D007075:Immunoglobulin M; D007135:Immunoglobulin Variable Region; D007142:Immunoglobulin gamma-Chains; D007145:Immunoglobulin kappa-Chains; D011993:Recombinant Fusion Proteins; D005678:G(M2) Ganglioside; D003165:Complement System Proteins