Poster Session C
Immunobiology
Chia Chi Sun, PhD
EMD Serono Research and Development Institute, Inc
Billerica, Massachusetts, United States
No financial relationships with ineligible companies to disclose
M5542 demonstrated superior inhibition of TNFa production compared to CTLA4Ig, anti-OX40L or the combination of both single agents in an allogenic MLR assay in vitro (Figure1A, similar observation with IL-6 and IFNg, data not shown). M5542 bound targets CD80 (KD = 522 nM), CD86 (KD = 434 nM), and OX40L (KD = 41 nM), with similar affinities as the single agents CTLA4Ig (CD80 KD = 552 nM), (CD86 KD = 548 nM) and anti-OX40L (KD = 50 nM). M5542 significantly reduced IFN-g in a SLE PBMC activation assay in vitro (Figure 1B). Interestingly, M5542 showed increased % target occupancy of CD80 and OX40L, compared to equimolar concentrations of CTLA4Ig or anti-OX40L alone, leading to the enhanced potency of M5542 in the MLR assay (Figure1C-D). M5542 demonstrated superior efficacy compared to single agents CTLA4Ig or anti-OX40L alone in suppressing human IFN-g levels and disease development in a humanized xeno-GvHD mouse model (Figure 2).
Conclusion: M5542 effectively blocked CD28 and OX40 mediated T-cell activation and reduced T-cell driven inflammation, demonstrating promise in treating autoimmune diseases.
The bi-functional fusion molecule M5542 demonstrated superior inhibition of proinflammatory cytokine, TNF production compared to single agents or combination in an in vitro MLR assay (A). TNFa%, CD80%, CD86% was normalized to isotype control levels. M5542 reduced IFNg production more than single agents in an in vitro SLE PBMC MLR assay (B). The effect of M5542 may be attributed to increased potency on CD80 (C) and OX40L (D) receptor occupancy.
M5542 demonstrated superior inhibition of human IFNg compared to either CTLA4Ig or anti-OX40L in a xenogenic graft vs host disease humanized mouse model.
M. Downing: EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, 3; L. Zhang: EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, 3; A. Desphpande: EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, 3; H. Zhang: EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, 3; O. Tarcic: Inter-lab Ltd, Israel, Merck KGaA, 3; M. toister-achituv: Merck, 3; A. Gross: EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, 3; G. Chen: EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, 3, 11; C. Sun: EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, 3, 11.