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Background T cell engagers (TCEs) are clinically successful bispecific antibodies, albeit primarily for treating blood cancers. TCEs provide a strong signal 1 for redirecting polyclonal T cells to kill cancer. However, receiving signal 1 for prolonged periods of time without a costimulatory signal leads to T cell anergy and exhaustion. Partly due to limited costimulatory signals in the tumor microenvironment, TCEs have had little therapeutic success in solid tumor indications so far. Recent single cell RNA sequencing data from multiple solid tumor types revealed that tumor infiltrating T cells express high levels of CD2 but not CD28 or other costimulatory receptors. Based on a proprietary antibody that binds a unique epitope on CD2, we have developed a novel bispecific antibody platform (BiTco) that provides costimulation to T cells via CD2 in the context of a tumor-associated antigen.Methods CD2 BiTco molecules were expressed and purified from CHO cultures to high purity. In vitro TCE-mediated killing models using co-cultures of BT474 clone 5 or HCC-1954 cell lines as target and sorted human immune cells as effectors were used to assess the impact of costimulation by CD2 BiTco molecules. In some cases, CD58 knockout HCC-1954 were used as target cells to isolate the impact of endogenous CD2-CD58 signaling. For in vivo testing, we established a BT474 clone 5 xenograft model using immunodeficient mice, in which a human T cell compartment was reconstituted by injection of human PBMCs.Results In vitro, we found that both CD2 BiTco and control CD28 bispecifics enhanced T cell activation and T cell-mediated tumor cell killing comparably. However, the CD2 BiTco molecule triggered markedly less cytokine release, making it a potentially safer clinical option. Moreover, we demonstrated that our CD2 BiTco format also provides robust costimulation to CD28-negative CD8 T cells, a population that constitutes the majority of CD8 T cells found in elder patients. In assay conditions mimicking settings of low TCE tumor antigen expression or loss of CD58 expression by tumors – both documented tumor resistance mechanisms – we demonstrated that costimulation by CD2 BiTco allowed to recover anti-tumor cytotoxicity. Finally, we showed in our in vivo model that combination treatment of CD2 BiTco with a sub-efficacious dose of a CD3 TCE resulted in highly effective control of tumor growth by human T cells.Conclusions In summary, combination therapy with our differentiated CD2 BiTco platform can improve CD3 TCE response and limit acquired resistance enabling efficacy in solid tumors.Ethics Approval Human material was collected in compliance with the German Transfusion Law or provided by the Etablissement Français du Sang which is regulated by the code de la santé publique/French Ministry of Health. For in vivo study, all procedures were conducted in accordance with the Guide for the Care and Use of Laboratory Animals of the European Council Directive (2010/63/UE) and were approved by French Animal Ethical Committee (APAFIS#47793-2024022716325549 v2).