The generation and anti-myeloma activity of a chimeric anti-CD54 antibody, cUV3.
Despite new treatment options, including autologous and allogeneic stem cell transplants, multiple myeloma remains an incurable disease. The authors developed and characterized a murine anti-human ICAM-1 (CD54) monoclonal antibody, UV3, which is highly effective in SCID mice with advanced human myeloma xenografts (SCID/ARH-77). To improve the effector functions and pharmacokinetic parameters and to reduce its immunogenicity in humans, the authors engineered this monoclonal antibody into a mouse/human IgG1kappa chimeric (c) antibody, cUV3. Following coexpression and purification of the genetically spliced heavy and light chain constructs, the authors compared cUV3 and UV3 in various in vitro assays, including relative cell-binding affinities and effector functions, namely antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. The authors compared their in vivo retention times and biodistribution patterns in normal mice. In each assay, the authors found that cUV3 was essentially equivalent to UV3. Finally, these antibodies were tested in a SCID/ARH-77 model of advanced myeloma, with daily treatments of 4 mug/g for 4 consecutive days commencing 14 days after tumor cell inoculation. cUV3 was at least as effective as UV3; 40% and 20% of the mice, respectively, were cured, with no sign of disease at day 150. The authors intend to evaluate the efficacy of cUV3 further in SCID/ARH-77 mice using other doses and dosing schedules to try to improve the cure rate. Eventually, they hope to test the efficacy of cUV3 in patients with multiple myeloma.
Smallshaw
Joan E
JE
Cancer Immunobiology Center, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-8576, USA.
Coleman
Elaine
E
Spiridon
Camelia
C
Vitetta
Ellen S
ES
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000915:Antibody Affinity; D000920:Antibody-Dependent Cell Cytotoxicity; D000970:Antineoplastic Agents / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology*; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality; D009368:Neoplasm Transplantation; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; C499602:UV3 monoclonal antibody; D018799:Intercellular Adhesion Molecule-1