The power of integrated CD2 costimulation to optimize anti-tumor immunity
The immune synapse between cytotoxic T lymphocytes (CTLs) and tumor cells is a specialized, organized interface critical for targeted killing. Upon antigen recognition through the T cell receptor (TCR) interacting with peptide-MHC I on the tumor cell, TcR complexes, adhesion proteins and an array of costimulatory and coinhibitory molecules reorganize into a supramolecular activation cluster (SMAC) which leads to the formation of an immunological synapse between the T cell and tumor cell. The synapse regulates the strength and duration of intracellular T cell signaling to drive efficient T cell responses, including tumor cell killing.
Why choose CD2 signaling to optimize anti-tumor immunity?
The CD2 receptor is an essential component of immune synapse formation, involved in organizing and stabilizing the immune synapse and regulating important costimulatory signals in the T cell. CD2 is initially positioned adjacent to the TcR complex to enhance TcR antigen recognition. It subsequently localizes to the outer edge of the mature synapse (called the peripheral SMAC or pSMAC) where it interacts with CD58 (LFA-3) to promote intracellular T cell signaling and T cell effector function.
Loss of the CD2-CD58 pathway is associated with immune evasion and tumor progression. Several publications have demonstrated this pathway to mediate responses to immunotherapies in preclinical models (Shen et al, 2022) and cancer patients (Majzner 2020, Frangieh 2021), to sustain cytotoxicity even when TcR signals are suboptimal, and to counteract the development of T cell exhaustion. CD2 has also been shown to serve as the primary costimulatory pathway in CD28– T cells (Leitner 2015).
Our own internal studies reveal that CD2 expression is maintained on the majority of human T cells. CD2 costimulation is superior to other forms of costimulation to mediate durable effector T cell responses. Thus, CD2 may be considered as a checkpoint for optimal immune synapse formation and T cell function.
What are the key design features of EVOLVE?
The design of our EVOLVE platform has been inspired by a generation of scientific discoveries which have elegantly described the structural and molecular biology of immune synapse formation and the unique role of CD2 costimulation in T cell biology. EVOLVE is engineered as a humanized trispecific T cell engager with integrated CD2 costimulation to therapeutically co-opt the key mechanisms central to efficient immune synapse formation, T cell signaling and T cell effector function.
Key features of EVOLVE include affinity-tuned CD3 binding and selective binding to the CD2 costimulatory receptor present on T cells. This optimizes T cell responses while mitigating the toxicities of cytokine release syndrome and preventing the generation of T cell dysfunction. EVOLVE-mediated T cell activation is dependent on tumor antigen binding. Importantly, EVOLVE is modular to enable alternative targeting and exhibits strong developability to allow for the manufacturing of these therapeutics at scale.
EVOLVE104 will be the first EVOLVE molecule to enter the clinic, in 2025.
Publications & Presentations
American Association for Cancer Research (AACR) Annual Meeting 2026
American Association for Cancer Research (AACR) Annual Meeting 2026
American Association for Cancer Research (AACR) Annual Meeting 2026
EVOLVE: T Cell Engager with Integrated CD2 Costimulation
The Essential Protein Engineering Summit (PEGS) Boston 2025
American Association for Cancer Research (AACR) Annual Meeting 2025
39th Annual Meeting of the Society for Immunotherapy of Cancer (SITC)
39th Annual Meeting of the Society for Immunotherapy of Cancer (SITC)
American Association for Cancer Research (AACR) Annual Meeting 2025
American Association for Cancer Research (AACR) Annual Meeting 2025
American Society of Hematology (ASH) Annual Meeting 2024
39th Annual Meeting of the Society for Immunotherapy of Cancer (SITC)
American Association for Cancer Research (AACR) Annual Meeting 2023
EVOLVE: a novel costimulatory T cell engager platform engineered for the treatment of solid tumors
American Association for Cancer Research (AACR) Special Conference on Tumor Immunology and Immunotherapy
American Association for Cancer Research (AACR) Annual Meeting 2023
- Lui Y. et. al. The structural biology of T-cell antigen detection at close contacts. Immunol. Rev. 331:e70014 (2025).
- Shen Y. et. al. Cancer cell-intrinsic resistance to BiTE therapy is mediated by loss of CD58 costimulation and modulation of the extrinsic apoptotic pathway. Immunother. Cancer. 10:e004348 (2022).
- Mazjner R.G. et. al. CD58 aberrations limit durable responses to CD19 CAR in large B cell lymphoma patients treated with axicabtagene ciloleucel but can be overcome through novel CAR engineering. Blood 136 (Suppl 1):53 (2020).
- Frangieh C.J. et. al. Multimodal pooled Perturb-CITE-seq screens in patient models define cancer immune evasion. Nat Genet. 53:332 (2021).
- Leitner J. et. al. CD58/CD2 is the primary costimulatory pathway in human CD28-CD8+ T cells. Immunol. 195:477 (2015).
- Structures shown in figure: pdb 1ccz, 1hnf, and 6jxr