Antiproliferative activity of a humanized anti-CD74 monoclonal antibody, hLL1, on B-cell malignancies.
The humanized anti-CD74 monoclonal antibody (mAb) hLL1 is under evaluation as a therapeutic agent. The effects of hLL1-at times in comparison with the CD20 mAb rituximab-were assessed on non-Hodgkin lymphoma (NHL) and multiple myeloma (MM) cell lines and in tumor-bearing SCID mice. In vitro, hLL1 caused growth inhibition and induction of apoptosis in B-cell lines when cross-linked with an antihuman immunoglobulin G (IgG) second antibody. The sensitivity profile of the cell lines was different for hLL1 and rituximab, and antiproliferative activity was augmented when the 2 mAbs were combined. Unlike rituximab, hLL1 did not induce antibody-dependent cellular cytotoxicity or complement-mediated cytotoxicity. In xenograft models of NHL and MM, treatment with hLL1 yielded significant survival benefits without cross-linking agents. Efficacy was greater in the MM model, in which median survival time was increased more than 4.5-fold. Thus, hLL1 has therapeutic potential as a naked mAb for B-cell malignancies because of high antigen expression on malignant cells, specifically MM, with limited expression on normal tissue, and because of its antiproliferative activity. Further, hLL1 may be a therapeutic candidate for rituximab-resistant disease because the 2 antibodies apparently act through distinct mechanisms and exhibit different expression and sensitivity profiles, and activity can be augmented when the mAbs are combined.
Stein
Rhona
R
Garden State Cancer Center, Center for Molecular Medicine and Immunology, 520 Belleville Ave, Belleville, NJ 07109, USA. rstein@gscancer.org
Qu
Zhengxing
Z
Cardillo
Thomas M
TM
Chen
Susan
S
Rosario
Adriane
A
Horak
Ivan D
ID
Hansen
Hans J
HJ
Goldenberg
David M
DM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D000944:Antigens, Differentiation, B-Lymphocyte / Q000276:immunology*; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D006801:Humans; D007231:Infant, Newborn; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy / Q000473:pathology; D009368:Neoplasm Transplantation; D015996:Survival Rate; D014183:Transplantation, Heterologous
D000911:Antibodies, Monoclonal; D000944:Antigens, Differentiation, B-Lymphocyte; D000970:Antineoplastic Agents; D000949:Histocompatibility Antigens Class II; C045084:invariant chain