Effective immunotherapy in the treatment of neoplastic diseases requires coupling antigen recognition to the activation of specific effector mechanisms. IgG antibodies can mediate effector responses either by the activation of cellular receptors for the Fc domain (FcgammaRs) or by activation of complement components. Recent results from the principal investigator's laboratory have demonstrated the importance of FcR activation, as opposed to complement activation, as the principal mechanism for triggering cytotoxicity. Protection from pulmonary metastasis in the B16 murine model of melanoma by MaB TA99 requires the presence of activation FcgRs is required and poly-clonal anti-gp75 antibodies. The molecular mechanisms behind this FcgR triggered tumor cytotoxicity will be dissected in several models of neoplastic disease to determine the specific FgcRs, effector cells and Fc interactions involved. Specifically, the investigators propose to 1) determine the contributions of specific effector cells and individual FcgRs in mediating protection from tumor spread in metastatic melanoma by characterizing individual FcgR knockouts and conditional knockouts of FcgRs on specific effector cells; 2) to construct a series of switch variants of the protective IgG2a mAb TA99 and to mutate specific Fc residues to disrupt specific Fc-FcR interactions; 3) to characterize the role of the inhibitory FcgammaRII receptor in modulating cytotoxicity of TA99 by evaluating the efficacy of this antibody in FcgammaRII deficient mice; 4) to create a more cytotoxic antibody by engineering the IgG Fc domain to optimize binding to activation FcgRs, while minimizing binding to the inhibitory FgRII; 5) to determine the generality of FcR dependent anti-tumor cytotoxicity by characterizing the effector pathways required to mediate protection in xenograft models of non-Hodgkins follicular lymphoma with the anti-CD20 mAb2B8 and breast cancer using the anti-p185HER2 mAb 4D5 using FcR and complement deficient strains and 6) to develop murine strains humanized for their FcR ligand binding domains by generating knock-in and transgenic mice expressing the human FcR specificities and testing these mice for their ability to display anti-tumor protection in xenograft models using humanized and chimeric mAbs. These studies will serve as the rationale for engineering Fc domains to mediate specific effector responses.
| Chen, Tiffany F; Sazinsky, Stephen L; Houde, Damian et al. (2017) Engineering Aglycosylated IgG Variants with Wild-Type or Improved Binding Affinity to Human Fc Gamma RIIA and Fc Gamma RIIIAs. J Mol Biol 429:2528-2541 |
| Dahan, Rony; Barnhart, Bryan C; Li, Fubin et al. (2016) Therapeutic Activity of Agonistic, Human Anti-CD40 Monoclonal Antibodies Requires Selective Fc?R Engagement. Cancer Cell 29:820-831 |
| DiLillo, David J; Ravetch, Jeffrey V (2015) Differential Fc-Receptor Engagement Drives an Anti-tumor Vaccinal Effect. Cell 161:1035-1045 |
| Li, Fubin; Ravetch, Jeffrey V (2011) Inhibitory Fc? receptor engagement drives adjuvant and anti-tumor activities of agonistic CD40 antibodies. Science 333:1030-4 |
