Properties and structure-function relationships of veltuzumab (hA20), a humanized anti-CD20 monoclonal antibody

• Published in: Blood Vol. 113; no. 5; pp. 1062 - 1070
• Main Authors: Goldenberg, David M., Rossi, Edmund A., Stein, Rhona, Cardillo, Thomas M., Czuczman, Myron S., Hernandez-Ilizaliturri, Francisco J., Hansen, Hans J., Chang, Chien-Hsing
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 29.01.2009; Americain Society of Hematology; American Society of Hematology
• Series: Lymphoid Neoplasia
• Subjects: Amino Acid Substitution; Animals; Antibodies, Monoclonal - genetics; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Antigens, CD20 - genetics; Antigens, CD20 - immunology; Antineoplastic Agents - immunology; Antineoplastic Agents - pharmacology; B-Lymphocytes - immunology; Biological and medical sciences; Cell Line, Tumor; Chlorocebus aethiops; Complement System Proteins - genetics; Complement System Proteins - immunology; Complementarity Determining Regions - genetics; Complementarity Determining Regions - immunology; Complementarity Determining Regions - pharmacology; Disease Models, Animal; Drug Screening Assays, Antitumor; Hematologic and hematopoietic diseases; Humans; Lymphoid Neoplasia; Lymphoma - drug therapy; Lymphoma - genetics; Lymphoma - immunology; Medical sciences; Mice; Mutation, Missense; Rituximab; Structure-Activity Relationship; Anti-CD20; Monoclonal antibody; Hematology; Humanized antibody; Structure function relationship
• DOI: 10.1182/blood-2008-07-168146
• ISSN: 0006-4971

Veltuzumab is a humanized anti-CD20 monoclonal antibody with complementarity-determining regions (CDRs) identical to rituximab, except for one residue at the 101st position (Kabat numbering) in CDR3 of the variable heavy chain (VH), having aspartic acid (Asp) instead of asparagine (Asn), with framework regions of epratuzumab, a humanized anti-CD22 antibody. When compared with rituximab, veltuzumab has significantly reduced off-rates in 3 human lymphoma cell lines tested, aswell as increased complement-dependent cytotoxicity in 1 of 3 cell lines, but no other in vitro differences. Mutation studies confirmed that the differentiation of the off-rate between veltuzumab and rituximab is related to the single amino acid change in CDR3-VH. Studies of intraperitoneal and subcutaneous doses in mouse models of human lymphoma and in normal cynomolgus monkeys disclosed that low doses of veltuzumab control tumor growth or deplete circulating or sessile B cells. Low- and high-dose veltuzumab were significantly more effective in vivo than rituximab in 3 lymphoma models. These findings are consistent with activity in patients with non-Hodgkin lymphoma given low intravenous or subcutaneous doses of veltuzumab. Thus, changing Asn101 to Asp101 in CDR3-VH of rituximab is responsible for veltuzumab's lower off-rate and apparent improved potency in preclinical models that could translate into advantages in patients.