Jean-Pierre Mach
Bruno Robert Institute of Biochemistry University of Lausanne, Epalinges, Switzerland

Antibody-MHC/Peptide Conjugates as a New Bridge Between Antibody and T-Lymphocyte Attack on Cancer Cells

Over the last 20 years, we and others have demonstrated that intravenously injected radiolabeled monoclonal antibodies (mAbs) directed against tumor markers overexpressed by human cancer cells, can localize, specifically into tumors. Furthermore, it was recently shown that injection of large amounts of unlabeled mAbs against differentiation markers or oncoproteins, such as CD20 or ErbB-2, can induce significant percentages of partial tumor remissions. However, the percentages of complete remissions induced by the various forms of antibody therapy remain very modest.

In parallel, numerous clinical trials of active vaccination with well-defined tumor restricted T-cell epitopes have demonstrated that tumor specific cytotoxic T-lymphocyte responses can be induced in patients. However, the number of tumor remissions observed in these trials is still limited. This may be due to the absence or low expression of either MHC molecules or their associated antigenic peptides by tumor cells.

Thus, in order to bridge the targeting properties of antibodies with the cytotoxic effector function of T lymphocytes, we propose to target on cancer cells highly antigenic MHC/peptide complexes conjugated to anti-tumor antibodies. We have already demonstrated in vitro that conjugates consisting of Fab’ fragments from different high affinity anti-tumor marker mAbs, such as anti-CEA, ErbB-2 or CD20, chemically coupled to a monomeric form of HLA-A2/influenza matrix peptide complexes can induce efficient lysis by human CTL, of cancer cells expressing these markers (Robert et al. Cancer Immunity, Vol. 1, p. 2, 2001).

The theoretical advantages of this immunotherapy strategy are first, that the monomeric MHC-peptide complexes conjugated to antibody fragments will not bind to circulating T lymphocytes due to their low affinity for T-cell receptor (TCR); thus, only when oligomerized on target tumor cells, can they induce the activation and cytotoxic activity of peptide specific T lymphocytes due to multiple binding sites. Second, the size of the conjugate of about 95 kDa is optimal for in vivo tumor localization, as we have demonstrated for F(ab’)2 fragments from anti-CEA mAbs. Third, the antibody-MHC conjugate will target multiple copies of the same selected antigenic peptide to the surface of the tumor cells, without the limitation of autologous antigenic peptides, which have to compete with a host of normal cellular peptides for expression on MHC. Fourth, the oligomerization of antibody-MHC peptide conjugates on tumor cells will provide binding sites, not only for the TCRs from specific CTL, but also for CD8 molecules which have been shown to play an essential role in the interaction with MHC peptide complexes. Overall, tumor cells targeted with antibody-MHC conjugates containing selected immunodominant viral peptides should have the same vulnerability to specific anti-viral CTL as cells specifically infected by the virus.

In terms of clinical applications, the antibody-MHC/peptide conjugates should be used in conjunction with active T-cell immunotherapy. In case of weak or partial tumor responses to immunotherapy, the conjugates may be useful for targeting more abundant and more antigenic MHC/peptides on the tumor cells for triggering or reinforcing the patient T-lymphocyte response against his own tumor cells.