B7-DC Cross-linking antibody immunotherapy

Project: Research project

Project Details

Description

DESCRIPTION (provided by applicant): B7-DC XAb is a patient derived IgM antibody capable of cross linking surface B7-DC molecules on human and murine dendritic cells. This human antibody has been fully characterized and pre-clinically tested for its utility as an immune modulator/cancer immunotherapeutic. Among its characteristics is the ability to generate effective cytotoxic T cell mediated anti-tumor immunity in tumor bearing mice; and to change the polarity of mouse helper T lymphocytes (HTL) from Th2 to Th1 in vivo (and in vitro) resulting in tumor regression. Because B7-DC XAb activates both human and mouse DC in vitro in a similar manner, we will test the hypothesis that the antibody will modulate the human immune system in a manner similar to the pattern observed in the mouse when the antibody is administered to patients with metastatic melanoma. Herein, we propose a proof-of-principle, phase I clinical trial evaluating the safety and immunomodulatory properties of B7-DC XAb administered to patients with metastatic malignant melanoma. In addition to evaluating the safety of treating patients with this potent immune modulator, we will evaluate the effects of treatment on dendritic cell activation, the function of tumor- specific T cells and the production of cytokines. The source of the antibody is unique in that the patient who naturally produces the antibody has kindly donated plasma to be used in this study. The patient's plasma has been collected, tested for transfusion-related pathogens and aliquoted in unit doses based on the quantity and specific activity of B7-DC XAb. This approach will allows us to test the safety/immunomodulatory activity of B7-DC XAb in humans and compare the results to our pre-clinical data, without the cost of GMP-grade antibody manufacturing. If the study is successful, the results will justify efforts towards synthesis of recombinant B7-DC XAb and its development as a novel pharmaceutical. Over the last several years we've been able to identify and fully characterize a unique, spontaneously occurring human antibody capable of human dendritic cell activation leading to protective anti-tumor immunity in animal studies of metastatic cancer (e.g. melanoma). The antibody (B7-DC XAb) was isolated from the blood of an otherwise healthy patient with a low grade lymphoid malignancy responsible for the production of B7-DC XAb. The currently proposed clinical trial represents an attempt to "translate" our laboratory work into the clinic and will evaluate the safety and immune modulatory properties of B7-DC XAb in patients with metastatic melanoma. If successful, this "proof-of-principle" clinical trial will justify further development of B7-DC XAb as a cancer therapeutic with potential universal application for all malignant disorders.
StatusFinished
Effective start/end date9/1/078/31/10

Funding

  • National Institutes of Health: $285,593.00
  • National Institutes of Health: $285,291.00

ASJC

  • Medicine(all)

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