Cure of SCID mice bearing human B-lymphoma xenografts by an anti-CD74 antibody-anthracycline drug conjugate.
OBJECTIVE
The purpose of this research was to test the therapeutic efficacy of an anthracycline-antibody conjugate for the treatment of human B-cell lymphoma in a preclinical animal model.


METHODS
Doxorubicin (dox) conjugates of the murine and humanized versions of the anti B-cell antibody LL1, targeting CD74, were prepared, along with a nonspecific control dox-antibody conjugate, targeting carcinoembryonic antigen. Antibody conjugates carried approximately 8-10 drug molecules attached site-specifically at thiols of reduced interchain disulfide bonds. Conjugates were tested, initially in vitro, and then for therapeutic efficacy in a systemic model, using a lethal i.v. dose of Raji cells in SCID mice.


RESULTS
Dox-LL1 conjugates were shown to be stable and 3-fold more effective in vitro against the human B-cell Burkitt's lymphoma line, Raji, compared with the nonspecific control conjugate that did not target CD74 or B cells. When SCID mice were given an i.v. dose of 2.5 million Raji cells, they would die of disseminated disease within 15-25 days postinjection. A single dose of dox-LL1 conjugate, 117-350 micro g, given 5 days to 14 (advanced disease) days after injection of the Raji cells resulted in cure of most animals out to 180 days after injection of the cells, whereas animals in treatment control groups were not cured. The dose of dox-LL1 found useful in this work corresponds with a significantly lower drug dose than reported previously with other drug-antibody conjugates


CONCLUSIONS
CD74 appears to be a uniquely useful target antigen for delivery of drugs, effecting cures of animals with single, low doses of conjugate.
Griffiths
Gary L
GL
Immunomedics, Inc., Morris Plains, New Jersey 07950, USA. ggriffiths@immunomedics.com
Mattes
M Jules
MJ
Stein
Rhona
R
Govindan
Serengulam V
SV
Horak
Ivan D
ID
Hansen
Hans J
HJ
Goldenberg
David M
DM
D000818:Animals; D018943:Anthracyclines / Q000494:pharmacology*; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000737:chemistry; D000944:Antigens, Differentiation, B-Lymphocyte / Q000096:biosynthesis / Q000737:chemistry*; D004220:Disulfides / Q000737:chemistry; D004317:Doxorubicin / Q000494:pharmacology; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis / Q000737:chemistry*; D006801:Humans; D007150:Immunohistochemistry; D007167:Immunotherapy; D016393:Lymphoma, B-Cell / Q000276:immunology*; D051379:Mice; D016513:Mice, SCID; D008956:Models, Chemical; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000628:therapy; D013997:Time Factors
D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D000911:Antibodies, Monoclonal; D000944:Antigens, Differentiation, B-Lymphocyte; D004220:Disulfides; D000949:Histocompatibility Antigens Class II; C045084:invariant chain; D004317:Doxorubicin