Preclinical trials using an immunoconjugate of T101 and methotrexate in an athymic mouse/human T-cell tumor model.
We made an immunoconjugate (IC) using the anti-CD5 monoclonal antibody T101 and the chemotherapeutic drug methotrexate. Methotrexate was conjugated to T101 using an active ester intermediate, yielding a drug: antibody molar ratio of 12.4. Although T101 immunoreactivity was not significantly altered by conjugation, the IC did not demonstrate antigen-specific cytotoxicity in vitro. Methotrexate activity, assayed in vitro, decreased approximately 100-fold following conjugation. The IC was tested for in vivo efficacy in athymic mice bearing human T-cell (MOLT 4) xenografts. Experimental arms used in the study included i.p. injections of saline, T101, methotrexate, the IC, and a mixture of T101 and methotrexate. Doses ranged from 500 micrograms T101 (17.5 micrograms methotrexate) to 2 mg T101 (70 micrograms methotrexate). Injections were administered only after palpable tumors were established. In experiments at all doses, totaling 66 animals per arm, injection of the IC significantly inhibited tumor growth, and resulted in more tumor regressions and fewer animal deaths than the other four experimental arms. These data demonstrate that the IC promotes a potential advantage over the use of methotrexate through an increase in the therapeutic index.
Shawler
D L
DL
Biotherapeutics Inc., La Jolla, California.
Johnson
D E
DE
Sweet
M D
MD
Myers
L J
LJ
Tudor
S D
SD
Beidler
D E
DE
Koziol
J A
JA
Dillman
R O
RO
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000951:Antigens, Neoplasm; D004195:Disease Models, Animal; D006801:Humans; D000922:Immunotoxins / Q000627:therapeutic use*; D008727:Methotrexate / Q000627:therapeutic use*; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy*
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D000922:Immunotoxins; D008727:Methotrexate