A New Class of Bifunctional Major Histocompatibility Class I Antibody Fusion Molecules to Redirect CD8 T Cells

Abstract

Bifunctional antibody fusion proteins engaging effector T cells for targeted elimination of tumor cells via CD3 binding have shown efficacy in both preclinical and clinical studies.

Immunotherapies: Exploiting the Immune System for Cancer Treatment

“…Postinfection, these CD8 + T cells become memory-like and get sequestered in peripheral tissue yet remain functional [ 104 ]. These antigen-experienced CD8 + T cells can go on to recognize MHC class I—peptide complexes on the surface of target cells [ 105 ]. By coupling an antitumor antibody fragment to an MHC molecule loaded with a viral peptide (i.e., CMV peptide) and coating the tumor with the complex, a tumor can resemble a virally infected cell, thus marking it for destruction by CVM-specific CD8 + T cells ( Figure 4 ) [ 106 – 108 ].…”

“…It has now been shown that in order to create a successful complex, one must add the pMHC1 complex to only one of two antibody chains, in particular, the unfused heavy chain with a “knob” mutation in order to produce less side products [ 105 ]. This technology allows for the expression of heterodimeric IgGs with two dissimilar heavy chains [ 105 ].…”

“…It has now been shown that in order to create a successful complex, one must add the pMHC1 complex to only one of two antibody chains, in particular, the unfused heavy chain with a “knob” mutation in order to produce less side products [ 105 ]. This technology allows for the expression of heterodimeric IgGs with two dissimilar heavy chains [ 105 ]. MHC1 complexes are said to be not as stable as antibodies [ 110 ], and by inserting an artificial disulfide bond in the space separating the linker of the MHC peptide and the MLA heavy chain [ 111 , 112 ], the first melting point can be increased and less aggregates can be produced [ 105 ].…”

“…This technology allows for the expression of heterodimeric IgGs with two dissimilar heavy chains [ 105 ]. MHC1 complexes are said to be not as stable as antibodies [ 110 ], and by inserting an artificial disulfide bond in the space separating the linker of the MHC peptide and the MLA heavy chain [ 111 , 112 ], the first melting point can be increased and less aggregates can be produced [ 105 ]. This allows for more product to be generated while mitigating any excess, unwanted products.…”

“…This allows for more product to be generated while mitigating any excess, unwanted products. This proposed complex offers the opportunity for monovalent antibody binding [ 105 ] and the delivery of practical peptide-MHC class I complexes to tumor cells. The proposed pMHC1-fused IgG antibodies can initiate CD8 + T cells to squander tumor cells at sub-nanomolar amounts and at a smaller effector to target cell ratio [ 105 ].…”