CEACAM5-targeted therapy of human colonic and pancreatic cancer xenografts with potent labetuzumab-SN-38 immunoconjugates.
OBJECTIVE
To improve the efficacy and reduce the gastrointestinal toxicity of the cancer prodrug, CPT-11, we have developed immunoconjugates of its active form, SN-38, and an anti-CEACAM5 antibody for targeted chemotherapy.


METHODS
SN-38 conjugates of the anti-CEACAM5 monoclonal antibody, labetuzumab (hMN-14), varying in the nature of the cross-linker attachment at the drug's 20-hydroxyl position, were evaluated in vitro, in metastatic and/or s.c. human colonic and pancreatic cancer xenografts in nude mice using appropriate controls, and in a CEACAM5-negative tumor model.


RESULTS
A pilot study in a s.c. LS174T model of human colonic carcinoma established the relative effectiveness of different conjugates. In the lung metastatic model of GW-39 human colonic carcinoma in nude mice, therapy with two specific labetuzumab-SN-38 conjugates, using 0.25 mg SN-38 equivalent/kg, q4d x 8, significantly extended median survival time versus controls (P < 0.002). In an expanded evaluation in the s.c. LS174T xenograft model, specific SN-38 conjugates produced significant tumor growth control and increases in median survival time versus other controls, including CPT-11 at a 33-fold greater cumulative dose (P < 0.01). An improvement was also observed in the therapy of a s.c. human pancreatic tumor xenograft. In a CEACAM5-negative systemic lymphoma xenograft, one labetuzumab-SN-38 conjugate examined was ineffective, whereas the conjugate specific for the tumor model produced 100% survival.


CONCLUSIONS
The promising labetuzumab-SN-38 conjugates developed showed selective therapeutic efficacy in human tumor models at nontoxic doses that were a fraction of the CPT-11 doses used.
Govindan
Serengulam V
SV
Immunomedics, Inc., Morris Plains, New Jersey 07950, USA. sgovindan@immunomedics.com.
Cardillo
Thomas M
TM
Moon
Sung-Ju
SJ
Hansen
Hans J
HJ
Goldenberg
David M
DM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use; D002272:Carcinoembryonic Antigen / Q000276:immunology*; D002277:Carcinoma / Q000188:drug therapy* / Q000276:immunology; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000276:immunology; D016503:Drug Delivery Systems / Q000379:methods; D005260:Female; D058851:GPI-Linked Proteins; D006801:Humans; D018796:Immunoconjugates / Q000627:therapeutic use*; D000077146:Irinotecan; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000276:immunology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C527875:CEACAM5 protein, human; D002272:Carcinoembryonic Antigen; D058851:GPI-Linked Proteins; D018796:Immunoconjugates; D000077146:Irinotecan; C110010:labetuzumab; D002166:Camptothecin