Development of a minimally immunogenic variant of humanized anti-carcinomamonoclonal antibody CC49

Monoclonal antibody (MAb) CC49 reacts with a pancarcinoma antigen, tumor as sociated glycoprotein (TAG)-72. To circumvent human anti-murine antibody (H AMA) responses in patients, we earlier developed a humanized CC49 (HuCC49 b y grafting the complementarity-determining regions (CDRs) of MAb CC49 onto variable light (VL) and variable heavy (VH) frameworks of the human MAbs LE N and 21/28 ' CL, respectively. With the aim of minimizing its immunogenici ty further, we have now generated a variant HuCC49 MAb by grafting the spec ificity-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-b inding activity and shows minimal reactivity with anti-idiotypic antibodies in patients' sera. Development of this variant, which is a potentially use ful clinical reagent for diagnosis and therapy of human carcinomas. demonst rates that for humanization of a xenogeneic antibody grafting of the potent ial SDRs should be sufficient to retain its antigen-binding properties. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.