Development of alpha4beta1-integrin specific ligand-Fcgamma protein bioconjugates for the treatment of human lymphoma.

摘要

In recent years, the FDA has approved several new antibody therapies for the treatment of human malignancies. However, antibody therapy is hindered by immune responses to the antibody itself and the large size of antibodies, which limits tumor penetration. For these reasons, the use of antibody fragments has emerged as a potential new therapeutic approach. Most of these antibody fragments utilize only the antigen-recognition portion of the antibody. However, antibody effector functions like antibody dependent cellular cytotoxicty (ADCC) and complement dependent cytotoxicity (CDC) are mediated through the constant region (Fe portion) of the antibody, which is eliminated in these antibody fragment approaches. To develop the Fc portion of the antibody as a therapeutic tool, a high affinity ligand specific to a protein expressed selectively on the cell surface of diseased cells is necessary. One such target is alpha4beta1-integrin (VLA-4), which is highly expressed in its active form on several human malignancies, especially lymphoma, and has been linked to cancer disease exacerbation. In normal, healthy cells expression of alpha4beta1-integrin is normally limited and in its inactive state, making the active form of this integrin a strong cancer target. The Lam laboratory has developed high affinity peptidomimetic ligands to activated alpha4beta1 integrin, LLP1A and LLP2A. A novel, peptide-directed immunotherapeutic approach covalently linking these ligands to the Fe portion of human IgG (Fcgamma) is reported here. Furthermore, these peptide-Fcgamma conjugates are capable of selectively inducing CDC and ADCC in alpha4beta1-expressing cancer cells.