Members of the TAM family of receptor tyrosine kinases (RTKs) play important roles in tumorigenesis and homeostatic regulation of the immune system. Two closely related ligands, Protein S (PROS1) and Growth Arrest Specific 6 (GAS6), bind and activate the TAMs, with GAS6 activating all TAMs and PROS1 activating MerTK and Tyro3. TAM RTKs are aberrantly expressed in many types of cancer where they may promote survival, metastasis, and chemoresistance. These receptors are also expressed on innate immune cells, particularly macrophages and dendritic cells, where they play important roles in clearance of apoptotic cells and negative regulation of inflammation. In tumors, activation of TAM signaling cascades appears to promote an antiinflammatory and immunosuppressive microenvironment, in turn driving tumor growth. Thus, inhibition of TAM signaling pathways through selective targeting with monoclonal antibodies could result in direct antitumor effects and promote antitumor immunity, whereas activation of TAMs could have antiinflammatory and immunosuppressive effects. We have used a variety of antibody-discovery strategies to identify potent and selective antagonists and agonists of human and rodent TAMs. Robust preclinical model systems for characterizing the mechanistic and functional effects of these antibodies have been established using engineered and nonengineered cell lines and primary cells. These include models to assess TAM activation and downstream signaling in cells and effects on cytokine secretion in LPS-stimulated U937 monocyte-derived and primary macrophages and primary dendritic cells. Effects of TAM inhibition on T-cell responses in mixed lymphocyte reactions are also being evaluated, as are in vivo mouse models. Utilizing these models, we have identified anti-TAM antibodies with antagonist or agonist activity, suggesting they may have potential in modulating the activity of these pathways.
Citation Format: Diego Alvarado, Laura Vitale, Michael Murphy, Thomas O'Neill, Andrew Proffitt, Jay Lillquist, Gwenda Ligon, Craig Polson, James R. Storey, Jenifer Widger, Laura Mills-Chen, Karuna Sundarapandiyan, Andrea Crocker, Colleen Patterson, Biwei Zhao, Russell A. Hammond, Li-Zhen He, Venky Ramakrishna, Joel Goldstein, Lawrence Thomas, Henry C. Marsh, Tibor Keler, Richard Gedrich. Identification and characterization of monoclonal antibodies targeting the Tyro3, Axl and MerTK (TAM) family of receptor tyrosine kinases [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B194.