BACKGROUND: Epithelial ovarian cancer (EOC) is an aggressive and heterogeneous disease. <10% of EOC demonstrate HER2/neu 3+ receptor over-expression. However, moderate to low (i.e., 2+ and 1+) HER2/neu expression is reported in up to 50% of EOC. The objective of this study was to compare the anti-tumor activity of SYD985, a novel HER2-targeting antibody-drug conjugate (ADC), to trastuzumab emtansine (T-DM1) in EOC models with differential HER2/neu expression. METHODS: The cytotoxicity of SYD985 and T-DM1 was evaluated using ten primary EOC cell lines with 0/1+, 2+, and 3+ HER2/neu expression in antibody-dependent cellular cytotoxicity (ADCC), proliferation, viability and bystander killing experiments. Finally, the in vivo activity of SYD985 and T-DM1 was also studied in ovarian cancer xenografts. RESULTS: SYD985 and T-DM1 induced similar ADCC in the presence of peripheral blood lymphocytes (PBL) against EOC cell lines with differential HER2/neu expression. In contrast, SYD985 was 3 to 42 fold more cytotoxic in the absence of PBL when compared to T-DM1 (p<0.0001). Unlike T-DM1, SYD985 induced efficient bystander killing of HER2/neu 0/1+ tumor cells when admixed with HER2/neu 3+ EOC cells. In vivo studies confirmed that SYD985 is significantly more active than T-DM1 against HER2/neu 3+ EOC xenografts. CONCLUSIONS: SYD985 is a novel ADC with remarkable activity against EOC with strong (3+) as well as moderate to low (i.e., 2+ and 1+) HER2/neu expression. SYD985 is more potent than T-DM1 in comparative experiments and unlike T-DM1, it is active against EOC demonstrating moderate/low or heterogeneous HER2/neu expression.
BACKGROUND:Epithelial ovarian cancer (EOC) is an aggressive and heterogeneous disease. <10% of EOC demonstrate HER2/neu 3+ receptor over-expression. However, moderate to low (i.e., 2+ and 1+) HER2/neu expression is reported in up to 50% of EOC. The objective of this study was to compare the anti-tumor activity of SYD985, a novel HER2-targeting antibody-drug conjugate (ADC), to trastuzumab emtansine (T-DM1) in EOC models with differential HER2/neu expression. METHODS: The cytotoxicity of SYD985 and T-DM1 was evaluated using ten primary EOC cell lines with 0/1+, 2+, and 3+ HER2/neu expression in antibody-dependent cellular cytotoxicity (ADCC), proliferation, viability and bystander killing experiments. Finally, the in vivo activity of SYD985 and T-DM1 was also studied in ovarian cancer xenografts. RESULTS: SYD985 and T-DM1 induced similar ADCC in the presence of peripheral blood lymphocytes (PBL) against EOC cell lines with differential HER2/neu expression. In contrast, SYD985 was 3 to 42 fold more cytotoxic in the absence of PBL when compared to T-DM1 (p<0.0001). Unlike T-DM1, SYD985 induced efficient bystander killing of HER2/neu 0/1+ tumor cells when admixed with HER2/neu 3+ EOC cells. In vivo studies confirmed that SYD985 is significantly more active than T-DM1 against HER2/neu 3+ EOC xenografts. CONCLUSIONS: SYD985 is a novel ADC with remarkable activity against EOC with strong (3+) as well as moderate to low (i.e., 2+ and 1+) HER2/neu expression. SYD985 is more potent than T-DM1 in comparative experiments and unlike T-DM1, it is active against EOC demonstrating moderate/low or heterogeneous HER2/neu expression.
Authors: Heidi L Perez; Pina M Cardarelli; Shrikant Deshpande; Sanjeev Gangwar; Gretchen M Schroeder; Gregory D Vite; Robert M Borzilleri Journal: Drug Discov Today Date: 2013-11-15 Impact factor: 7.851
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Authors: Sunil Verma; David Miles; Luca Gianni; Ian E Krop; Manfred Welslau; José Baselga; Mark Pegram; Do-Youn Oh; Véronique Diéras; Ellie Guardino; Liang Fang; Michael W Lu; Steven Olsen; Kim Blackwell Journal: N Engl J Med Date: 2012-10-01 Impact factor: 91.245
Authors: Siming Zhao; Murim Choi; John D Overton; Stefania Bellone; Dana M Roque; Emiliano Cocco; Federica Guzzo; Diana P English; Joyce Varughese; Sara Gasparrini; Ileana Bortolomai; Natalia Buza; Pei Hui; Maysa Abu-Khalaf; Antonella Ravaggi; Eliana Bignotti; Elisabetta Bandiera; Chiara Romani; Paola Todeschini; Renata Tassi; Laura Zanotti; Luisa Carrara; Sergio Pecorelli; Dan-Arin Silasi; Elena Ratner; Masoud Azodi; Peter E Schwartz; Thomas J Rutherford; Amy L Stiegler; Shrikant Mane; Titus J Boggon; Joseph Schlessinger; Richard P Lifton; Alessandro D Santin Journal: Proc Natl Acad Sci U S A Date: 2013-01-28 Impact factor: 11.205
Authors: H B Salvesen; S L Carter; M Mannelqvist; A Dutt; G Getz; I M Stefansson; M B Raeder; M L Sos; I B Engelsen; J Trovik; E Wik; H Greulich; T H Bø; I Jonassen; R K Thomas; T Zander; L A Garraway; A M Oyan; W R Sellers; K H Kalland; M Meyerson; L A Akslen; R Beroukhim Journal: Proc Natl Acad Sci U S A Date: 2009-03-04 Impact factor: 11.205
Authors: A H Sims; A J M Zweemer; Y Nagumo; D Faratian; M Muir; M Dodds; I Um; C Kay; M Hasmann; D J Harrison; S P Langdon Journal: Br J Cancer Date: 2012-05-01 Impact factor: 7.640