A DeImmunized chimeric anti-C3b/iC3b monoclonal antibody enhances rituximab-mediated killing in NHL and CLL cells via complement activation.
Complement-dependent cytotoxicity (CDC) is a key mechanism of Rituximab (RTX) action in killing non-Hodgkin's lymphoma (NHL) cells both in vitro and probably in vivo. A DeImmunized, mouse/human chimeric monoclonal antibody (Mab), H17, specific for cell-associated complement C3 cleavage products, C3b and iC3b, was generated to enhance RTX-mediated killing of target cells by CDC. When NHL cell lines were treated with RTX and H17 in the presence of complement for 1 h, there was 40-70% more cell death than that observed with RTX alone. The enhancing effect of H17 was also seen over longer treatment periods. H17 was tested ex vivo against primary cells from NHL and chronic lymphocytic leukemia (CLL) patients. In RTX-resistant NHL samples, H17 enhanced RTX-mediated killing; in the remaining samples RTX + complement alone promoted more than 80% killing, and no significant enhancement was observed. The H17 antibody also increased RTX-mediated killing in four out of nine CLL samples. H17 may have therapeutic applications in NHL and CLL treatment as an adjunctive therapy to RTX. It might also enhance the activity of other therapeutic antibodies that work through CDC.
Peng
Wu
W
Elusys Therapeutics, 25 Riverside Drive, PO Box 102, Pine Brook, NJ 07058, USA. wpeng@elusys.com
Zhang
Xin
X
Mohamed
Nehal
N
Inghirami
Giorgio
G
Takeshita
Kenichi
K
Pecora
Andrew
A
Nardone
Linda L
LL
Pincus
Steve E
SE
Casey
Leslie S
LS
Spitalny
George L
GL
D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000627:therapeutic use*; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D003167:Complement Activation; D003165:Complement System Proteins / Q000276:immunology; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy*; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy*; D051379:Mice; D000069283:Rituximab; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000069283:Rituximab; D003165:Complement System Proteins