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Blood, 29 January 2009, Vol. 113, No. 5, pp. 1062-1070.
Prepublished online as a Blood First Edition Paper on October 21, 2008; DOI 10.1182/blood-2008-07-168146.
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Submitted July 14, 2008
Accepted September 28, 2008
Properties and structure-function relationships of veltuzumab (hA20), a humanized anti-CD20 monoclonal antibody
David M Goldenberg*, Edmund A Rossi, Rhona Stein, Thomas M Cardillo, Myron S. Czuczman, Francisco J. Hernandez-Ilizaliturri, Hans J Hansen, and Chien-Hsing Chang
Garden State Cancer Center, Center for Molecular Medicine and Immunology, Belleville, NJ, United States
Immunomedics, Inc., Morris Plains, NJ, United States
Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, United States
* Corresponding author; email: dmg.gscancer{at}att.net.
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 to rituximab, veltuzumab has significantly reduced off-rates in 3 human lymphoma cell lines tested, as well as increased complement-dependent cytotoxicity in 1/3 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 i.p. and s.c. 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 i.v. or s.c. doses of veltuzumab. Thus, changing Asn101 to Asp101 in CDR3-VH of rituximab is responsible for veltuzumab's lower off-rate and presumably improved potency in preclinical models that could translate into advantages in patients.
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