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Engineering Novel Immunogens

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Vaccines are the most effective, and most cost-effective, health interventions ever devised by humanity, but efforts to develop prophylactic HIV vaccines remain stymied by the multiplex immunoevasion strategies of the virus.  We continue to collaborate on innovative means to engineer novel immunogens to elicit protective humoral responses, further understand the biophysics of the process of antibody ontogeny, and determine the molecular-level mechanism of antibody-mediated virus neutralization.
 

Deciphering the Interplay Between Molecular Interactions Controlling T cell Outputs

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Allogeneic hematopoietic cell transplantation (HCT) is an effective therapy for life-threatening, non-malignant disorders of the hematopoietic and immune systems. However, major limitations of allogeneic HCT in patients with nonmalignant disorders have been host-versus-graft reactions (graft rejection) and immune reactions of donor lymphocytes against host antigens, also called graft-versus-host disease (GVHD), both of which can be fatal. HCT recipients are generally treated with long term immunosuppressive regimens which weakens host immune responses to pathogens, thereby increasing the risk of serious infections – and is not uniformly successful in controlling GVHD. CD28 and CTLA-4 are leukocyte cell-surface costimulatory receptors that profoundly influence the course of immune responses: CD28 magnifies the effects of TCR signaling and enhances both cell cycle progression and T cell survival; CTLA-4 (CD152) provides opposing inhibitory signals. CD28 and CTLA-4 bind the shared, related ligands B7.1 (CD80) and B7.2 (CD86).

The long-term goal of this project is to develop computationally-redesigned B7-based antagonists and agonists specific for CD28 or CTLA-4 for use as short-term immunotherapeutics in various clinical contexts, initially focusing on the control of host-versus-graft reactions and GVHD following allogeneic HCT. In the short term, we are deciphering the interplay between the molecular interactions occuring at the cell surface that control T cell outputs. 

 

Reengineering High-Throughput Screening for TCR Antibodies

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The era of targeted anti-cancer therapies was ushered in by the development of therapeutic antibodies specific for antigens expressed primarily on tumors, improving the lives of countless cancer patients. Methodological improvements have made it possible to produce antibodies specific for peptides from tumor antigens or viral oncoproteins presented in the context of major histocompatibility complex (MHC) class I proteins (in humans: HLA-A, -B, -C), which are often restricted to tumor cells. These antibodies mimic how T cell receptors (TCR) recognize peptide/MHC complexes. These “TCR mimic” or mTCR antibodies combine the specificity of a TCR with the affinity of an antibody, allowing the targeting of antigens expressed by cancerous cells, while sparing normal cells.

Such antibodies are useful as ex vivo and in vivo diagnostics, and as probes of antigen presentation. mTCR antibodies are difficult to elicit by design, because of the precise nature, and small size, of the surface they must bind to on a pMHC. The current best approaches require extensive high-throughput screening to isolate true TCR-like antibodies. We are improving this developing technology by reengineering the process at every step, from simplified epitope discovery to better methods to capture and deliver radionuclides. Our initial efforts target cancers caused by oncoviruses.