title: Anti-Endosialin Antibody-Drug Conjugate: Potential in Sarcoma and Other Malignancies.
abstract: Endosialin/TEM1/CD248 is a cell surface protein expressed at high levels by the malignant cells of about 50% of sarcomas and neuroblastomas. The antibody-drug conjugate (ADC) anti-endosialin-MC-VC-PABC-MMAE was selectively cytotoxic to endosialin-positive cells in vitro and achieved profound and durable antitumor efficacy in preclinical human tumor xenograft models of endosialin-positive disease. MC-VC-PABC-MMAE was conjugated with anti-endosialin with 3-4 MMAE molecules per ADC. The anti-endosialin-MC-VC-PABC-MMAE conjugate was tested for activity in four human cell lines with varied endosialin levels. The HT-1080 fibrosarcoma cells do not express endosialin, A-673 Ewing sarcoma cells and SK-N-AS neuroblastoma cells are moderate expressers of endosialin, and SJSA-1 osteosarcoma cells express very high levels of endosialin. To determine whether endosialin expression was maintained in vivo, A-673 Ewing sarcoma, SK-N-AS neuroblastoma, and SJSA-1 osteosarcoma cells were grown as xenograft tumors in nude mice. The SK-N-AS neuroblastoma and the A-673 Ewing sarcoma lines were selected for in vivo efficacy testing of the anti-endosialin-MC-VC-PABC-MMAE conjugate. The treatment groups included a vehicle control, unconjugated anti-endosialin, an admix control consisting of anti-endosialin and a dose of free MMAE equivalent to the dose administered as the ADC, and the anti-endosialin-MC-VC-PABC-MMAE conjugate. The unconjugated anti-endosialin had no antitumor activity and resulted in similar tumor growth as the vehicle control. The admix control produced a modest tumor growth delay. Administration of the anti-endosialin-MC-VC-PABC-MMAE conjugate resulted in a marked prolonged tumor response of both xenograts. These proof-of-concept results break new ground and open a promising drug discovery approach to these rare and neglected tumors.
authors.affiliation: Genzyme Corporation, Framingham, Massachusetts.
authors.forename: Cecile
authors.initials: C
authors.lastname: Rouleau
authors.affiliation: Genzyme Corporation, Framingham, Massachusetts.
authors.forename: Diego A
authors.initials: DA
authors.lastname: Gianolio
authors.affiliation: Genzyme Corporation, Framingham, Massachusetts.
authors.forename: Robert
authors.initials: R
authors.lastname: Smale
authors.affiliation: Genzyme Corporation, Framingham, Massachusetts.
authors.forename: Stephanie D
authors.initials: SD
authors.lastname: Roth
authors.affiliation: Genzyme Corporation, Framingham, Massachusetts.
authors.forename: Roy
authors.initials: R
authors.lastname: Krumbholz
authors.affiliation: Genzyme Corporation, Framingham, Massachusetts.
authors.forename: Jay
authors.initials: J
authors.lastname: Harper
authors.affiliation: Genzyme Corporation, Framingham, Massachusetts.
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Munroe
authors.affiliation: Genzyme Corporation, Framingham, Massachusetts.
authors.forename: Tessa L
authors.initials: TL
authors.lastname: Green
authors.affiliation: Genzyme Corporation, Framingham, Massachusetts.
authors.forename: Bruce C
authors.initials: BC
authors.lastname: Horten
authors.affiliation: Genzyme Corporation, Framingham, Massachusetts.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Schmid
authors.affiliation: Genzyme Corporation, Framingham, Massachusetts. teicherba@mail.nih.gov.
authors.forename: Beverly A
authors.initials: BA
authors.lastname: Teicher
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression; D006801:Humans; D018796:Immunoconjugates; D007150:Immunohistochemistry; D051379:Mice; D015394:Molecular Structure; D012509:Sarcoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; C078203:CD248 protein, human; D018796:Immunoconjugates