BACKGROUND: Antibody-drug conjugates (ADCs) such as Kadcyla™ (ado-trastuzumab emtansine [T-DM1]) present covalently bound cytotoxic drugs, which may influence their immunogenicity potential compared with antibody therapies. Therefore, ADCs require assay strategies that allow measurement of responses to all the molecular components. RESULTS: The immunogenicity strategy for T-DM1 used a risk-based, tiered approach that included screening and titration to detect antitherapeutic antibodies; confirmation of positive responses; and characterization to assess whether the immune response is primarily to the antibody or to the linker-drug and/or new epitopes in trastuzumab resulting from conjugation. CONCLUSION: The tiered immunogenicity assay strategy for T-DM1 allowed detection of antitherapeutic antibodies to all components of the ADC in multiple nonclinical and clinical studies. Characterization strategies implemented in clinical studies provided additional insights into the specificity of the immune response.
BACKGROUND: Antibody-drug conjugates (ADCs) such as Kadcyla™ (ado-trastuzumab emtansine [T-DM1]) present covalently bound cytotoxic drugs, which may influence their immunogenicity potential compared with antibody therapies. Therefore, ADCs require assay strategies that allow measurement of responses to all the molecular components. RESULTS: The immunogenicity strategy for T-DM1 used a risk-based, tiered approach that included screening and titration to detect antitherapeutic antibodies; confirmation of positive responses; and characterization to assess whether the immune response is primarily to the antibody or to the linker-drug and/or new epitopes in trastuzumab resulting from conjugation. CONCLUSION: The tiered immunogenicity assay strategy for T-DM1 allowed detection of antitherapeutic antibodies to all components of the ADC in multiple nonclinical and clinical studies. Characterization strategies implemented in clinical studies provided additional insights into the specificity of the immune response.
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Authors: Emma Davé; Ralph Adams; Oliver Zaccheo; Bruce Carrington; Joanne E Compson; Sarah Dugdale; Michael Airey; Sarah Malcolm; Hanna Hailu; Gavin Wild; Alison Turner; James Heads; Kaushik Sarkar; Andrew Ventom; Diane Marshall; Mark Jairaj; Tim Kopotsha; Louis Christodoulou; Miren Zamacona; Alastair D Lawson; Sam Heywood; David P Humphreys Journal: MAbs Date: 2016-08-17 Impact factor: 5.857
Authors: Douglas D Leipold; Isabel Figueroa; Shabkhaiz Masih; Brandon Latifi; Victor Yip; Ben-Quan Shen; Randall C Dere; Montserrat Carrasco-Triguero; M Violet Lee; Ola M Saad; Luna Liu; Jintang He; Dian Su; Keyang Xu; Brian R Vuillemenot; Steven T Laing; Melissa Schutten; Katherine R Kozak; Bing Zheng; Andrew G Polson; Amrita V Kamath Journal: MAbs Date: 2018-10-02 Impact factor: 5.857