THE ROLE OF T-CELL ACTIVATION IN ANTI-CD3 X ANTITUMOR BISPECIFIC ANTIBODY THERAPY

Anti-CD3 X antitumor bispecific Ab can retarget T cell mediated lysis in an MHC-independent fashion and prevent tumor growth in animal model s. Two bispecific Ab preparations that differ in the presence or absen ce of Fc were compared in the 38C13 immunocompetant murine lymphoma mo del to evaluate how functional Fc and T cell activation impact on resp onse to bispecific Ab therapy. Bispecific (bs) IgG contained functiona l Fc and was purified from hybrid-hybridoma Ab product. BsF(ab')(2) la cked functional Fc, and was genetically constructed using the leucine zipper technique. In vitro, bsF(ab')(2) induced tumor cell lysis by ac tivated T cells more effectively than bslgG. However, bsF(ab')(2) fail ed to induce T cell activation in the absence of tumor cells, and did so more slowly than bslgG when tumor cells were present. In vivo, bslg G induced nonspecific T cell activation whereas bsF(ab')(2) did not. I n therapy experiments, bslgG inhibited tumor growth in mice although a single dose of bsF(ab')(2) had minimal antitumor effect. BsF(ab')(2) was capable of preventing tumor growth and improving survival when mic e were also treated with T cell activators (IL-2 or staphylococcal ent erotoxin B), or given repeated bsF(ab')(2) doses. We conclude the ther apeutic response to bispecific Ab was not dependent on functional Fc, but did require T cell activation. The use of bifunctional constructs that lack functional Fc therefore allows for separate manipulation of T cell retargeting and T cell activation and deserves further evaluati on as a potential immunotherapy for malignancy.