Regressions and cures of melanoma xenografts following treatment with monoclonal antibody beta-lactamase conjugates in combination with anticancer prodrugs.
Cephalosporin doxorubicin (C-Dox) and 7-(4-carboxybutanamido)-cephalosporin mustard (CCM) are prodrugs that are catalytically converted by Enterobacter cloacae beta-lactamase (bL) to the active anticancer agents doxorubicin and phenylenediamine mustard, respectively. Both prodrugs were less cytotoxic to the 3677 human melanoma line than their respective drugs and were activated in an immunologically specific manner by 96.5-bL, a mAb-bL conjugate that binds to 3677 cell surface antigens. Similar results were obtained using the CCM prodrug on SK-MEL 28 human melanoma cells. Experiments in mice with established s.c. 3677 tumors demonstrated that although no tumors were cured in mice receiving the 96.5-bL/C-Dox combination, the activities were greater than those obtained from systemic doxorubicin treatment or from administration of the nonbinding conjugate P1.17-bL in combination with C-Dox. In contrast, when CCM was used as a prodrug, cures of established 3677 tumors were obtained in 80% of the 96.5-bL treated animals. This combination was also able to induce regressions of large 3677 tumor masses (800 mm3) without any apparent toxic side effects. We conclude that 96.5-bL in combination with C-Dox or CCM has greater antitumor activity than systemic treatment with the corresponding drugs and that CCM is a more effective prodrug than C-Dox for treating human 3677 melanoma xenografts.
Kerr
D E
DE
Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, WA 98121, USA.
Schreiber
G J
GJ
Vrudhula
V M
VM
Svensson
H P
HP
Hellström
I
I
Hellström
K E
KE
Senter
P D
PD
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000951:Antigens, Neoplasm; D002511:Cephalosporins; D004317:Doxorubicin / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D018796:Immunoconjugates; D008545:Melanoma / Q000188:drug therapy*; D058950:Melanoma-Specific Antigens; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000276:immunology; D009368:Neoplasm Transplantation; D009588:Nitrogen Mustard Compounds / Q000008:administration & dosage*; D011355:Prodrugs / Q000008:administration & dosage*; D001618:beta-Lactamases / Q000008:administration & dosage*
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D002511:Cephalosporins; D018796:Immunoconjugates; D058950:Melanoma-Specific Antigens; D009363:Neoplasm Proteins; D009588:Nitrogen Mustard Compounds; D011355:Prodrugs; C038005:phenylenediamine mustard; D004317:Doxorubicin; D001618:beta-Lactamases