A rapid and efficient in vivo method for determining the biologic efficacy of monoclonal antibodies in animal models of cancer.
The selection of efficacious anti-tumor monoclonal antibodies (MAbs) for biological applications is a lengthy and labor-intensive process. In vitro characterization of one hybridoma fusion may reveal large numbers of tumor antigen-specific hybridomas. Very often, many of these tumor-specific antibodies need to be assessed in vivo using several different murine xenograft tumor prevention models to determine biological efficacy. The production and purification of sufficient quantities of many antigen-specific hybridomas is time-consuming, and several months can pass between initial determination of MAb specificity and bioactivity. Moreover, many tumor-specific MAbs selected using in vitro binding studies have no in vivo anti-tumor efficacy. These studies describe an in vivo screening method either to eliminate non-efficacious MAbs or to rank-order several tumor-specific MAbs in an expeditious manner. Proof-of-concept studies were conducted using two hybridomas secreting fully characterized neutralizing human anti-tumor MAbs (CNTO MAbs). Nu-/nu- mice were injected with CNTO MAb-secreting hybridoma cells in Matrigel cell matrix, followed by injection of target human tumor cells 4 days later (when circulating CNTO MAbs were detected in serum). Both the tumor take-rate and the mean tumor volumes were reduced significantly in mice treated with CNTO MAbsecreting hybridomas compared with mice treated with non-antibody-secreting cells. A panel of human antitumor antigen-specific MAbs with unknown biological efficacy was then evaluated by this method. The hybridomas exhibited a varied pattern of anti-tumor protection, indicating that some hybrids were secreting neutralizing anti-tumor MAbs, while others appeared to be less efficacious. These studies demonstrate a rapid, biologically relevant "yes/no" in vivo screening method for the evaluation of anti-tumor antigen MAbs.
Staquet
Kimberly
K
Department of Cellular Biology, Discovery Research, Centocor Research & Development Inc., Radnor, Pennsylvania 19087, USA. KStaquet@cntus.jnj.com
Giles-Komar
Jill
J
D000818:Animals; D000911:Antibodies, Monoclonal / Q000097:blood / Q000627:therapeutic use*; D000951:Antigens, Neoplasm / Q000276:immunology; D000970:Antineoplastic Agents / Q000302:isolation & purification / Q000627:therapeutic use*; D002460:Cell Line; D003094:Collagen; D004338:Drug Combinations; D005260:Female; D006801:Humans; D006825:Hybridomas / Q000276:immunology / Q000378:metabolism; D007797:Laminin; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000276:immunology / Q000473:pathology; D011509:Proteoglycans; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; C059485:matrigel; D003094:Collagen