Full T cell activation requires two signals: the first signal is antigen specific, delivered through the T-cell receptor (TCR) via the peptide/MHC; the second, or “co-stimulatory” signal(s) is required for T cell cytokine production and proliferation. In the absence of co-stimulation, activation through the TCR may lead to a state of T-cell anergy or non-responsiveness, or to the state of exhaustion.
The TriTETM (Tri-specific T-cell Engager) platform employs “Two-signal System” as the mechanism of action for T cell activation through the engagement of both the CD3/TCR and co-stimulatory receptor. Compares to T cell activation lacking the co-stimulatory signal, the extra engagement of a co-stimulatory receptor through a agonist agent has a great potential to amplify TCR signal and achieve durable and effective immune response.
Hodge JW, Greiner JW, Tsang KY, et al. Frontiers in Bioscience,
2006 11:788-803; DOI: 10.2741/1837
Natural killer (NK) cells are an integral component of the innate immune response to tumours. Natural killer (NK) cells are cytotoxic lymphocytes that are able to kill tumor cells without prior sensitization. It has been shown that NK cells play a pivotal role in a variety of cancers, highlighting their relevance in tumor immunosurveillance.
Three pathways for NK cells to induce apoptosis of tumor cells：
-Granzyme B/Perforin pathway
-Fas/FasL pathway
-ADCC pathway
Zambello R, Barila G, Manni S, et al. Cell, 2020 Mar; 9(3):768;
DOI: 10.3390/cells9030768
Vivier E, Raulet DH, Moretta A, et al. Science, 2011 331(6013):44-9; DOI:10.1126/science.1198687
NK cells express a variety of activating and inhibitory receptors, as well as co-stimulatory receptors. These receptors recognize cellular stress ligands as well as major histocompatibility complex class I (MHC I) and related molecules, which can lead to NK cell responses.
Killer inhibitory receptor (KIR) delivers inhibitory signals to prevent NK cells from attacking self cells by recognizing and binding to the MHC I complex of self cells, whose absence may result in NK activation, the so-called “missing-self recognition”.
Activating NK cell receptors include members of the human Killer Immunoglobulin-like Receptor (KIR) family or the mouse Ly49 family, CD94-NKG2C/E/H heterodimeric receptors, NKG2D, natural cytotoxicity receptors such as NKp30, NKp44, NKp46, the nectin/nectin-like binding receptors DNAM-1/CD226 and CRTAM.
The CCNKTM platform is designed to harness the immune functions of NK cells in cancer treatment. Specially, new antibody formats capable of stimulating the antitumor activity of innate immune cells are now in development in CytoCares with ultimate goal of long-lasting tumor control.The dual roles of macrophage in tumor microenvironment (TME)：
I. Direct phagocytosis to promote anti-tumor responses or indirect activation of other immune cells by recruiting and/or presenting tumor antigens
II.As T helper 2 (TH2) cells begin to dominate the TME, tumor associated macrophage (TAM) begin to exhibit an immunosuppressive protumor phenotype that promotes tumor progression, metastasis, and resistance to therapy.
Lopez-Yrigoyen M, Cassetta L, and Pollard JW. Ann. N.Y. Acad. Sci. , 1499 (2021) 18-41; doi: 10.1111/nyas.14377
Lopez-Yrigoyen M, Cassetta L, and Pollard JW. Ann. N.Y. Acad. Sci. , 1499 (2021) 18-41; doi: 10.1111/nyas.14377
CCMφTM pipeline products are macrophage modulating antibodies developed to enhance the natural and adaptive immunity against tumors, including:
- Antibodies targeting phagocytic activity of macrophages
- Antibodies targeting TAM-preferentially expressed targets
