Combination Of Tyrp1-Tcb, A Novel T Cell Bispecific Antibody For The Treatment Of Melanoma, With Immunomodulatory Agents

In the past decade, many checkpoint inhibitors (CPI) have been approved for melanoma, demonstrating the increasing potential of immunotherapy as a lifesaving treatment for this devastating disease. However, many patients relapse or need to discontinue treatment due to adverse effects. Patients failing CPI have very limited treatment options and very poor outcomes. This supports the need for novel and more effective immunotherapies, including combination approaches. Bispecific antibodies like blinatumomab have been approved for hematologic malignancies but positive benefit in solid tumors has been more challenging to demonstrate. Given the relative high T cell content in melanoma, we considered this indication highly promising to investigate whether synthetic immunity also works in solid tumors. Here we present a novel potent treatment approach based on an off the shelf T cell engaging bispecific antibody directed against a melanoma associated target. The tyrosinase-related protein 1 antigen (TYRP1), an enzyme expressed in normal melanosomes and involved in melanin synthesis, is overexpressed in more than 50% of metastatic melanoma patients. TYRP1-TCB is a new 2+1 format T cell bispecific antibody targeting TYRP1 on tumor cells and CD3 on T cells. CD3 bispecific molecules do not depend on HLA expression or antigen presentation and could therefore overcome immune evasion mechanisms in patients failing CPI; as such, T cell redirection via TYRP1-TCB has the potential to be the foundation for new and improved CIT combinations. In vitro TYRP1-TCB mediated strong killing of patient derived melanoma cells from a dermatology cell bank as observed by LDH release, T cell activation and cytokine secretion with EC50 ranging from 30-1500 pM. Pre-clinical investigation in vivo with a murine surrogate molecule showed potent efficacy in subcutaneous as well as aggressive lung metastatic B16 melanoma mouse models that do not respond to anti-PD1 or anti-PD-L1 therapy. Furthermore, the combination with immunomodulatory agents like FAP-IL2v and FAP-4-1BBL molecules demonstrated enhanced efficacy as compared to the respective single agents. These preclinical data support the clinical evaluation of TYRP1 targeted CD3 bispecific antibody as a single agent and in combination in metastatic relapsed/refractory melanoma patients. Citation Format: Valeria G. Nicolini, Inja Waldhauer, Anne Freimoser-Grundschober, Marine Richard, Linda Fahrni, Esther Bommer, Christina Claus, Johannes Sam, Sara Colombetti, Roger Sutmuller, Mitchell P. Levesque, Anja Irmisch, Conrad Bleul, Neil Campbell, Marina Bacac, Ekkehard Moessner, Christian Klein, Pablo Umana. Combination of TYRP1-TCB, a novel T cell bispecific antibody for the treatment of melanoma, with immunomodulatory agents [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-389.