Antibody Engineering

Research in my lab aims at understanding the factors that limit or enhance the effector functions of both naturally occurring and therapeutic antibodies, and at identifying the cellular and molecular components that underlie a successful antibody-mediated immune response. A major focus of our studies is to investigate the role of the antibody Fc domain through its diverse interactions with immune cells expressing the cellular receptors for antibodies, Fc receptors (FcR). In this context, we are mechanistically exploring Fc-related factors that determine the efficacy of checkpoint antibodies in cancer immunotherapy. We apply antibody engineering approaches to harness the identified mechanisms of these therapeutic antibodies to improve their anti-tumor activity and safety. This includes the generation of Fc-optimized and multi-specific antibodies with novel modes of action that we develop as the next-generation of immunotherapies.

Antibodies are central to immunotherapy, but they are extremely complex molecules, and many antibodies exhibit suboptimal properties that limit or preclude their translation to therapies. Our lab develops atomistic and AI-based tools for optimizing proteins or designing completely new ones. For example, we have developed reliable and completely automated tools for dramatic, one-shot improvement of stability, activity and production of antibodies, therapeutic enzymes and vaccine immunogens. We have also designed a novel platform for tuning CAR-T cell therapy efficacy and cytokine release. Some ongoing topics of research are developing general algorithms to humanize and optimize the affinity, stability and production of therapeutic antibodies while maintaining their human immune-system tolerability. Our long-term goal is to design completely human, yet highly functional and stable antibodies that could be quickly developed into clinical candidates.

Our lab specializes in the analysis of the antibody-mediated immune responses in different contexts, including pathogen invasion, vaccination, pathogenic gut bacteria invasion and cancer. We examine the immune cells of cancer patients to discover naturally occurring tumor-binding antibodies and their specific targets. The lab studies how these antibodies evolve, whether they follow a similar development path as in immune response against pathogens and how they acquire self-reactivity against tumor cells. The lab aims to understand why tumor-reactive antibodies fail in tumor eradication and which missing molecular and cellular components can reactivate their tumor-eradicating functions. Specifically, we focus on recovering antibody sequences from ovarian carcinoma, clear cell renal cell carcinoma and non-small cell lung cancer patients using single-cell and antibody-seq approaches followed by the generation of monoclonal antibodies and functional testing. These studies have the potential to uncover new tumor-associated targets and patient-derived monoclonal antibodies for the delivery of therapeutic agents specifically into tumor cells in cancer patients.

High target specificity and ability to recruit immune effector cells make antibodies ideal therapeutic agents. Within the field of cancer research, we are interested in two topics: (i) inhibition of cancer metastasis, and (ii) delaying the onset of resistance to anti-cancer drugs. Our studies make use of home-made or clinically approved monoclonal antibodies, which are administered either alone or in combinations with other drugs. Usually, we employ high-throughput screens that identify novel target proteins involved in either dissemination of tumor cells or relapses of tumor following treatment with anti-cancer drugs. Next, we generate antibodies to the novel targets and apply them on animal models of specific cancers. Eventually, we study the molecular mechanisms that underlay the action of relatively effective and safe anti-cancer treatments.