Unarmed, tumor-specific monoclonal antibody effectively treats brain tumors.
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.
Sampson
J H
JH
Department of Surgery (Neurosurgery), Duke University Medical Center, Durham, NC 27710, USA. john.sampson@duke.edu
Crotty
L E
LE
Lee
S
S
Archer
G E
GE
Ashley
D M
DM
Wikstrand
C J
CJ
Hale
L P
LP
Small
C
C
Dranoff
G
G
Friedman
A H
AH
Friedman
H S
HS
Bigner
D D
DD
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology*; D000912:Antibodies, Neoplasm / Q000008:administration & dosage / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000276:immunology*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D066246:ErbB Receptors / Q000235:genetics* / Q000276:immunology; D005260:Female; D006801:Humans; D051379:Mice; D009154:Mutation; D013601:T-Lymphocytes / Q000276:immunology
D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D000951:Antigens, Neoplasm; D066246:ErbB Receptors