Antibody-targeted chemotherapy with the calicheamicin conjugate hu3S193-N-acetyl gamma calicheamicin dimethyl hydrazide targets Lewisy and eliminates Lewisy-positive human carcinoma cells and xenografts.
OBJECTIVE
Linking a cytotoxic anticancer drug to an antibody that recognizes a tumor-associated antigen can improve the therapeutic index of the drug. We asked whether a conjugate of the cytotoxic antibiotic N-acetyl gamma calicheamicin dimethyl hydrazide (CalichDMH) and an antibody recognizing Lewis(y) (Le(y)) antigen could eliminate carcinomas that express Le(y). Because Le(y) is highly expressed on carcinomas of colon, breast, lung, ovary, and prostate, a CalichDMH conjugate targeting Le(y) could provide a treatment option for various cancers.


METHODS
The humanized anti-Le(y) antibody hu3S193 was conjugated to CalichDMH via the bifunctional AcBut linker. Selectivity and avidity of the conjugate (hu3S193-CalichDMH) for Le(y)-BSA or Le(y+) cells was tested by BIAcore or flow cytometry. Cytotoxicity of hu3S193-CalichDMH was compared with toxicity of a control conjugate on monolayers of Le(y+) and Le(y-) carcinoma cells. Inhibition of tumor growth by hu3S193-CalichDMH was assessed on three types of s.c. xenografts.


RESULTS
Hu3S193-CalichDMH had similar selectivity as hu3S193. The conjugate had lower affinity for Le(y)-BSA but not for Le(y+) cells. When tested on monolayers of human Le(y+) carcinoma cells, hu3S193-CalichDMH was more cytotoxic than a control conjugate. This difference in efficacy was not noted on Le(y-) cells. Efficacy of hu3S193-CalichDMH depended on the expression of Le(y) and on the sensitivity of the cells to CalichDMH. In vivo, hu3S193-CalichDMH inhibited growth of xenografted human gastric (N87), colon (LOVO), and prostate carcinomas (LNCaP). When used against N87 xenografts, hu3S193-CalichDMH arrested tumor growth for at least 100 days.


CONCLUSIONS
Hu3S193-CalichDMH can specifically eliminate Le(y+) tumors. These results support development of this conjugate for treatment of carcinomas.
Boghaert
Erwin R
ER
Wyeth Discovery Oncology and Wyeth Discovery Chemical and Screening Sciences, Pearl River, New York, USA. Boghaee@wyeth.com
Sridharan
Latha
L
Armellino
Douglas C
DC
Khandke
Kiran M
KM
DiJoseph
John F
JF
Kunz
Arthur
A
Dougher
Maureen M
MM
Jiang
Fan
F
Kalyandrug
Lyka B
LB
Hamann
Philip R
PR
Frost
Philip
P
Damle
Nitin K
NK
D000617:Aminoglycosides / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000494:pharmacology*; D000941:Antigens / Q000737:chemistry; D002277:Carcinoma / Q000378:metabolism; D045744:Cell Line, Tumor; D002469:Cell Separation; D003094:Collagen / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D004306:Dose-Response Relationship, Immunologic; D004338:Drug Combinations; D053281:Enediynes; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology*; D006868:Hydrolysis; D007167:Immunotherapy / Q000379:methods*; D007700:Kinetics; D007797:Laminin / Q000737:chemistry; D007983:Lewis Blood Group Antigens / Q000737:chemistry*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008956:Models, Chemical; D009368:Neoplasm Transplantation; D011485:Protein Binding; D011509:Proteoglycans / Q000737:chemistry; D012680:Sensitivity and Specificity; D020349:Surface Plasmon Resonance; D014018:Tissue Distribution
D000617:Aminoglycosides; D000911:Antibodies, Monoclonal; D000941:Antigens; D004338:Drug Combinations; D053281:Enediynes; D006834:Hydrazines; D007797:Laminin; D007983:Lewis Blood Group Antigens; C094162:Lewis Y antigen; D011509:Proteoglycans; C495698:hu3S193-N-acetyl gamma calicheamicin dimethyl hydrazide; C055955:calicheamicin gamma(1)I; C059485:matrigel; D003094:Collagen