The Marasco Laboratory is located in the Department of Cancer Immunology and AIDS at Dana-Farber Cancer Institute. Our general research interests are in the field of targeted immunotherapy. The Lab’s work has made major scientific advances in the treatment of infectious diseases and cancer. More recently, we have been developing humanized mice to support our targeted immunotherapy studies and to investigate the roles of human adult stem cells in regenerative medicine.
Specifically, the lab’s research interests are in human monoclonal antibody (Mab) immunotherapy and broad-spectrum anti-viral vaccine development. We use human Mabs in functional and structural studies to understand mechanisms of viral entry, identify common targets that provide broad-spectrum protection, and develop strategies that prevent the viruses from undergoing neutralization escape. Vaccinated/infected humans and humanized mice are the B-cell sources of antibody genes for these studies.
Our discoveries of common and highly conserved structural elements on the envelope glycoproteins that serve as cross-neutralizing targets for Mab therapy have allowed us to make therapeutic inroads into the prevention and treatment of a wide range of human pathogenic coronaviruses, flaviviruses, and influenza A viruses. The Marasco Laboratory has advanced therapeutic Mab development through NIH-NIAID product development programs in the areas of SARS, West Nile virus, and Influenza A infections. The Lab’s pioneering studies in influenza, which resulted in our finding of a "universal" vaccine target that can provide broad-spectrum protection against a wide range of influenza A viruses, has led to a paradigm shift in the field of influenza immunotherapy and vaccine development.
Our National Foundation of Cancer Research (NFCR) Center for Therapeutic Antibody Engineering (CTAE) at Dana-Farber Cancer Institute is working in a broad range of discovery and translational research in cancer. We have the tools, know-how and expertise to advance our novel immunotherapy discoveries from bench to bedside.
We have a major effort in constructing and improving humanized mice (a.k.a. humouse) and in improving their performance and utility in different biomedical research applications. Our internal research programs are in the areas of human B cell development, optimizing vaccines against infectious agents (influenza A, HIV-1, Denge) and human antibody immunotherapy. We are also using these humanized mice for investigations related to adult stem cell biology and regenerative medicine which are now becoming central efforts in the laboratory. For more details, please visit www.humouse.org.
There has been a recent surge in research involving “humanized” mice, which both underscores the growing need for and the finding that these human developmental and disease models can provide reliable and validated in vivo systems to study complex biological processes. We are developing humanized mouse models for different areas of investigations including regenerative medicine, cancer immunotherapy and stem cell biology, B-cell developmental biology as well as infectious diseases and related vaccine development. For more information please visit our website at www.humouse.org.
Human B-cell Ontogeny and Vaccine Development
We are constructing different types of “humanized mice” for investigations of B-cell ontogeny and their utility in evaluating infectious diseases and cancer vaccines. In one such model, the “BLT” mouse develop a functional human lymphoid system after human stem cell engraftment. We have shown that a single intramuscular immunization with recombinant viral envelope antigens, e.g., HIVgp140 and West Nile Virus envelope (WNV-E) proteins, together with the immune-stimulatory TLR9 agonist results in seroconversion and secretion of antigen-specific human antibodies. In vitro studies with human T-cells recovered from these mice demonstrate suboptimal proliferative responses and loss of co-stimulatory surface proteins ex vivo that could be partially reversed with human interleukin (IL)-2 and IL-7. We are currently investigating whether CD4 helper T-cell functions which are required for optimal B cell maturation can modulated in vivo by the exogenous delivery of human cytokines/growth factors.
In a second study, we performed on the analysis of single-sorted human B cells from humanized NOD/SCID gc-/- (hNSG) mice at both genetic and functional levels. B cells from different stages of development, from early immature in the bone marrow to naïve mature in the periphery were sorted as single cells, the antibody genes cloned and expressed as single chain antibody fragments (scFvFcs). Sequence analysis of the antibody genes suggested an impairment in the checkpoint control mechanisms based on longer HCDR3 regions with high levels of positive charges found in the peripheral naïve mature B cells, a characteristic of auto/polyreactive antibodies. This observation was functionally confirmed by performing autoantigen binding analysis with the purified scFvFcs. Moreover, our findings of poly/auto reactive antibodies were extended to show that many of these antibodies can also bind with high affinity binding to HIV envelope protein. This suggests that the hNSG model (and BLT/GTL models) can be used to study the ontogeny of anti-HIV antibodies at the molecular level.
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