Abstract B58: Early safety assessment of single and combination therapy using TDAR

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Abstract The discovery of targeted therapies against tumors offers promise of therapeutic benefit to patients however, it poses challenges in assessing immunologic and toxicologic risk during drug development. We determined that early safety assessment of combination therapy, prior to later stage toxicology studies, can be used to support Go/No-Go NME decision and thereby reduce time, efficiency, and resources used to choose and develop lead candidates. The rodent T-cell-dependent antibody response (TDAR) assay is used to assess the effect of candidate therapeutic agents on the immune system by measuring primary and secondary IgM and IgG antibody responses to exogenous antigen challenge. TDAR responses require intact function of multiple immune cells including antigen presenting cells and T and B lymphocytes, as well as a cytokine-dependent isotype class switch from IgM to IgG, resulting in production of an antigen-specific antibody response. Alterations in the amount of antibody produced therefore can reflect effects on any or all cell populations involved in TDAR. TDAR is commonly used in preclinical drug development especially where increased cause for concern exists (ICH guideline S8). Development of combination therapy that engages multiple targets impacting the immune system poses unique opportunity for increased efficacy but also unique risk for increased immunotoxicity including immune stimulation. For this work, a mouse TDAR evaluating primary and secondary KLH antibody responses in a KLH-Specific IgM and IgG sandwich enzyme-linked immunosorbent assay (ELISA) was first validated and then used to assess immunotoxicologic potential of multiple single immunosuppressive agents (cyclophosphamide (CTX), abatacept, azathioprine (AZT), etanercept, cyclosporine (CsA), and prednisone) and biological therapies (A, B, C, D, E, and F) and combination biologic therapies ( A+B, C+D, E+F). Doses of 100 mg/kg CsA, 250 mg/kg abatacept, 125 mg/kg etanercept, 100 mg/kg AZT, 20 mg/kg prednisone administered subcutaneously (s.c.) on Days 1 and 3 had mild immunosuppressive effects. 200 mg/kg of CTX administered s.c. had an expected robust immunosuppressive effect that was statistically significant than control. Combination of biologic therapies did not result in enhanced TDAR immunotoxicity compared to single biologic therapy alone for the molecules evaluated. Tier 1 immunotoxicology assessments similar to those in standard toxicity studies were added to the TDAR assessment. Together, these data support the use of the TDAR assay for early safety assessment of potential combination therapies against tumors. Citation Format: Amy L. Volk, Mindi Walker, Kerry Brosnan, Dorie Capaldi, Patricia Rafferty, Daniel Weinstock, Eva Emmell. Early safety assessment of single and combination therapy using TDAR. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B58.

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