Development of a minimally immunogenic variant of humanized anti-carcinoma monoclonal antibody CC49.
Monoclonal antibody (MAb) CC49 reacts with a pancarcinoma antigen, tumor associated glycoprotein (TAG)-72. To circumvent human anti-murine antibody (HAMA) responses in patients, we earlier developed a humanized CC49 (HuCC49) by grafting the complementarity-determining regions (CDRs) of MAb CC49 onto variable light (VL) and variable heavy (VH) frameworks of the human MAbs LEN and 21/28'CL, respectively. With the aim of minimizing its immunogenicity further, we have now generated a variant HuCC49 MAb by grafting the specificity-determining residues (SDRs) of MAb CC49 onto the frameworks of the human MAbs. Based on the evaluation of its binding affinity for TAG-72 and its reactivity with anti-idiotypic antibodies present in sera from patients who have been treated with murine CC49, this variant retains its antigen-binding activity and shows minimal reactivity with anti-idiotypic antibodies in patients' sera. Development of this variant, which is a potentially useful clinical reagent for diagnosis and therapy of human carcinomas, demonstrates that for humanization of a xenogeneic antibody grafting of the potential SDRs should be sufficient to retain its antigen-binding properties.
Kashmiri
S V
SV
National Institutes of Health, National Cancer Institute, Laboratory of Tumor Immunology and Biology, Building 10, Room 5B38, Bethesda, MD 20892, USA. sk85f@nih.gov
Iwahashi
M
M
Tamura
M
M
Padlan
E A
EA
Milenic
D E
DE
Schlom
J
J
D000818:Animals; D000910:Antibodies, Heterophile / Q000235:genetics; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D000912:Antibodies, Neoplasm / Q000276:immunology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000276:immunology / Q000627:therapeutic use; D022801:Complementarity Determining Regions / Q000032:analysis / Q000235:genetics; D015195:Drug Design; D005818:Genetic Engineering; D014644:Genetic Variation; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*
D000910:Antibodies, Heterophile; D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D000970:Antineoplastic Agents; C091202:B72.3 antibody; D022801:Complementarity Determining Regions