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Unarmed, tumor-specific monoclonal antibody effectively treats brain tumors
J H Sampson1, L E Crotty, S Lee
1Department of Surgery (Neurosurgery), Duke University Medical Center, Durham, NC 27710, USA. john.sampson@duke.edu
Abstract:
The epidermal growth factor receptor (EGFR) is often amplified and rearranged structurally in tumors of the brain, breast, lung, and ovary. The most common mutation, EGFRvIII, is characterized by an in-frame deletion of 801 base pairs, resulting in the generation of a novel tumor-specific epitope at the fusion junction. A murine homologue of the human EGFRvIII mutation was created, and an IgG2a murine mAb, Y10, was generated that recognizes the human and murine equivalents of this tumor-specific antigen. In vitro, Y10 was found to inhibit DNA synthesis and cellular proliferation and to induce autonomous, complement-mediated, and antibody-dependent cell-mediated cytotoxicity. Systemic treatment with i.p. Y10 of s.c. B16 melanomas transfected to express stably the murine EGFRvIII led to long-term survival in all mice treated (n = 20; P < 0.001). Similar therapy with i.p. Y10 failed to increase median survival of mice with EGFRvIII-expressing B16 melanomas in the brain; however, treatment with a single intratumoral injection of Y10 increased median survival by an average 286%, with 26% long-term survivors (n = 117; P < 0.001). The mechanism of action of Y10 in vivo was shown to be independent of complement, granulocytes, natural killer cells, and T lymphocytes through in vivo complement and cell subset depletions. Treatment with Y10 in Fc receptor knockout mice demonstrated the mechanism of Y10 to be Fc receptor-dependent. These data indicate that an unarmed, tumor-specific mAb may be an effective immunotherapy against human tumors and potentially other pathologic processes in the "immunologically privileged" central nervous system.
Insights
A novel antibody targeting the EGFRvIII mutation in cancer shows promise for immunotherapy. Treatment with this antibody, Y10, led to long-term survival in mice with melanomas, suggesting potential for treating brain tumors.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Epidermal growth factor receptor (EGFR) alterations, including the common EGFRvIII mutation, are prevalent in various human cancers.
- EGFRvIII results from an in-frame deletion, creating a unique tumor-specific antigen.
- Targeting tumor-specific antigens is a key strategy in cancer immunotherapy.
Purpose of the Study:
- To generate and characterize a monoclonal antibody (mAb) targeting the EGFRvIII tumor-specific antigen.
- To evaluate the in vitro and in vivo efficacy of the anti-EGFRvIII mAb (Y10) in preclinical cancer models.
- To elucidate the mechanism of action of Y10 immunotherapy.
Main Methods:
- Generation of a murine homologue of human EGFRvIII and production of the murine mAb Y10.
- In vitro assays to assess Y10's effects on DNA synthesis, proliferation, and cytotoxicity.
- In vivo studies using B16 melanoma models (subcutaneous and brain) treated with Y10, including cell depletion and Fc receptor knockout experiments.
Main Results:
- Y10 demonstrated in vitro inhibition of cancer cell growth and induced cytotoxicity.
- Systemic Y10 treatment eradicated subcutaneous EGFRvIII-expressing melanomas, leading to long-term survival.
- Intratumoral Y10 injection significantly increased survival in brain melanoma models, with a notable percentage of long-term survivors.
- Y10's in vivo efficacy was Fc receptor-dependent and independent of complement and major immune cell subsets.
Conclusions:
- The tumor-specific mAb Y10 exhibits potent anti-tumor activity against EGFRvIII-expressing cancers.
- Intratumoral administration of Y10 shows significant therapeutic potential for central nervous system tumors.
- Unarmed, tumor-specific mAbs represent a viable immunotherapy strategy for various cancers and potentially other diseases in immunologically privileged sites.