Anti-CD74 antibody-doxorubicin conjugate, IMMU-110, in a human multiple myeloma xenograft and in monkeys.
OBJECTIVE
IMMU-110 is a drug immunoconjugate composed of doxorubicin conjugated to the humanized anti-CD74 monoclonal antibody, hLL1, at a doxorubicin/monoclonal antibody ratio of approximately 8:1 (mol/mol). CD74 is a rapidly internalizing molecule associated with HLA-DR, which has high expression by several tumor types. Here, we describe safety evaluations of IMMU-110 in mice and monkeys as well as efficacy studies in a xenograft model of the human multiple myeloma cell line, MC/CAR.


METHODS
In vitro binding of IMMU-110 was determined by a cell-based ELISA and cytotoxicity of IMMU-110 assayed with a tetrazolium assay. Pharmacokinetics and biodistribution of radiolabeled IMMU-110 were examined in tumor-free BALB/c mice, and the therapeutic effectiveness was evaluated in severe combined immunodeficient mice bearing MC/CAR cells. Acute toxicity of IMMU-110 was studied in CD74-positive cynomolgus monkeys (Macaca fascicularis).


RESULTS
In vitro, IMMU-110 specifically binds to CD74 and is cytotoxic against MC/CAR cells. In vivo, IMMU-110 displayed a pharmacokinetic and biodistribution profile identical to that of unconjugated hLL1 monoclonal antibody, except for higher kidney uptake. Treatment with a single dose of IMMU-110 as low as 50 microg antibody/mouse (or 1.4 microg doxorubicin/mouse), 5 days postinjection of the multiple myeloma cells, resulted in cure of most mice. In mice, no host toxicity of IMMU-110 was observed at the highest protein dose tested (125 mg/kg). In cynomolgus monkeys, bone marrow toxicity was observed at 30 and 90 mg/kg doses.


CONCLUSIONS
The excellent safety and efficacy profile of IMMU-110 supports clinical testing of this immunoconjugate in the treatment of CD74-positive B-cell malignancies.
Sapra
Puja
P
Immunomedics, Inc., Morris Plains, New Jersey 07950, USA. psapra@immunomedics.com
Stein
Rhona
R
Pickett
Jennifer
J
Qu
Zhengxing
Z
Govindan
Serengulam V
SV
Cardillo
Thomas M
TM
Hansen
Hans J
HJ
Horak
Ivan D
ID
Griffiths
Gary L
GL
Goldenberg
David M
DM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000276:immunology* / Q000493:pharmacokinetics / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000944:Antigens, Differentiation, B-Lymphocyte / Q000276:immunology; D004317:Doxorubicin / Q000009:adverse effects / Q000276:immunology* / Q000493:pharmacokinetics; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D000882:Haplorhini; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006801:Humans; D018796:Immunoconjugates / Q000009:adverse effects / Q000276:immunology* / Q000493:pharmacokinetics; D007262:Infusions, Intravenous; D008252:Macaca fascicularis; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000276:immunology* / Q000662:veterinary; D014018:Tissue Distribution; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000944:Antigens, Differentiation, B-Lymphocyte; D000949:Histocompatibility Antigens Class II; C505097:IMMU-110; D018796:Immunoconjugates; C045084:invariant chain; D004317:Doxorubicin