Unarmed, tumor-specific monoclonal antibody effectively treats brain tumors

The epidermal growth factor receptor (EGFR) is often amplified and rearrang ed structurally in tumors of the brain, breast, lung, and ovary. The most c ommon mutation, EGFRvIII, is characterized by an in-frame deletion of 801 b ase 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 h uman and murine equivalents of this tumor-specific antigen. In vitro, Y10 w as found to inhibit DNA synthesis and cellular proliferation and to induce autonomous, complement-mediated, and antibody-dependent cell-mediated cytot oxicity. 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 mic e treated (n = 20; P < 0.001). Similar therapy with i.p. Y10 failed to incr ease median survival of mice with EGFRvIII-expressing B16 melanomas in the brain; however, treatment with a single intratumoral injection of Y10 incre ased 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 ind ependent of complement, granulocytes, natural killer cells, and T lymphocyt es through in vivo complement and cell subset depletions. Treatment with Y1 0 in Fc receptor knockout mice demonstrated the mechanism of Y10 to be Fe r eceptor-dependent. These data indicate that an unarmed, tumor-specific mAb may be an effective immunotherapy against human tumors and potentially othe r pathologic processes in the "immunologically privileged" central nervous system.