ANTIBODY FUSION PROTEINS FOR THE THERAPY OF CANCER

Project: Research project

Project Details

Description

DESCRIPTION: (Applicant's Abstract) Minimal residual disease is a
serious problem in the therapy of many common malignancies including
breast, lung, ovarian and gastrointestinal cancer. More effective
therapies are required to target minimal residual disease and
micrometastases. The applicant believes that combined recruitment and
costimulation using antibody fusion proteins may act synergistically to
amplify host response to tumors. The applicant will synthesize antibody
fusion molecules with variable domains directed against tumor associated
antigens, such as CEA or her2/neu, linked to sequences encoding the
chemokine RANTES and/or to the extracellular domain of the B7.1 T-cell
costimulatory ligand. RANTES, a C-C chemokine acts to recruit T-cells
and other immune effector cells to sites of inflammation. B7.1, the
ligand for the CD28 costimulatory receptor acts to deliver a second
signal required for T-cell activation following engagement of the T-cell
receptor (TCR). Fusion with RANTES is designed to increase
transendothelial migration and recruitment of the immune effector cells,
while fusion with B7.1 is expected to activate a specific host response
to tumor from effector cell population. The applicant will construct and
purify novel antibody fusion proteins specific for the tumor-associated
antigens, her2/neu and CEA, linked to the chemokine RANTES and/or the
extracellular domain of the B7.1 costimulatory ligand. Two promising
fusions to RANTES and to B7.1 have already been constructed and are
being actively characterized. He will evaluate the immunoreactivity,
receptor binding properties and biological activity of fusion proteins
in vitro. RANTES fusions will be studied for antigen binding, binding
to cellular receptors, and for ability to elicit chemotaxis. B7.1 fusion
proteins will be characterized for ability to bind to antigen, cognate
cellular receptors (CTLA4 and CD28), and to deliver a co-stimulatory
signal in vitro. He will characterize the properties of the recombinant
fusion proteins in vivo and their effectiveness in causing tumor
rejection. Localization of radiolabelled fusion proteins in vivo will
be studied in SCID mice implanted with her2/neu or CEA expressing and
non-expressing tumors. Tumor models that express the target antigens
will be studied in immunologically competent syngeneic mice. Fusion
proteins will be tested for efficacy in eliciting tumor rejection and
a cytolytic T-cell response. Both CEA and her2/neu are expressed at low
levels in certain normal tissues. Therefore, the applicant will model
efficacy and potential toxicity of anti CEA fusion proteins in a
transgenic CEA mouse. The use of antibody fusion proteins may overcome
limitations of gene transfer and/or standard antibody therapy and
represents a promising approach to the problem of minimal residual
disease.
StatusFinished
Effective start/end date1/15/9912/31/03

Funding

  • National Cancer Institute: $287,710.00
  • National Cancer Institute
  • National Cancer Institute: $287,034.00
  • National Cancer Institute

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