December 8, 2021

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Science: Targeting cancer with bispecific antibodies

Science: Targeting cancer with bispecific antibodies


Science: Targeting cancer with bispecific antibodies.   The tumor suppressor gene TP53 (the encoded protein product is p53) is the most common cancer driver gene after mutation.

However, decades after the discovery of the key role of p53 mutant protein in cancer, people still cannot obtain drugs that target it. Although there are drugs that inactivate proteins encoded by oncogenes such as mutated epidermal growth factor receptor (EGFR) or BRAF, the proteins encoded by tumor suppressor genes have been inactivated by mutations.

It is very challenging to reactivate such proteins through the use of pharmaceutical preparations. Therefore, people are actively looking for new methods to target these inactive proteins, including the protein encoded by TP53.

In a new study, researchers from Johns Hopkins University School of Medicine in the United States tried to develop an immunotherapy method to target the protein encoded by the mutated TP53 gene. p53 is an intracellular protein, mainly located in the nucleus, so traditional antibody-based therapies cannot be achieved. However, the protein is degraded by the proteasome into peptides, some of which can be presented on the cell surface by the human leukocyte antigen (HLA). This, in principle, allows a properly designed protein to recognize peptide fragments of intracellular proteins when it binds to HLA on the cell surface.

 

Science: Targeting cancer with bispecific antibodies
The mechanism of action of the H2 bispecific antibody, the picture is from Science, 2021, doi:10.1126/science.abc8697.



The substitution of arginine to histidine at codon 175 (R175H) is the most common TP53 mutation and the most common mutation in all tumor suppressor genes. The polypeptide HMTEVVRHC (underlined with the mutant amino acid) derived from the p53R175H mutation can bind to a specific HLA allele (HLA-A*02:01) to form a peptide-HLA complex on the cell surface.

HLA-A*02:01 is the most common type of HLA-A in the American population. Therefore, the p53R175H/HLA-A*02:01 complex is a particularly attractive therapeutic target, shared by many cancer patients. However, as a neoantigen, this peptide-HLA complex usually exists on the cell surface at a low density. To achieve meaningful therapeutic effects, an effective form of treatment is required.

T cells can be activated in the presence of very low amounts of antigen. Therefore, these authors tried to produce a T cell-based therapy that links T cells to cancer cells through a newly developed antibody that specifically binds to the p53R175H peptide-HLA complex.

 

Using a large phage library displaying various antibody variable region fragments, the authors identified H2, which is an antibody fragment that has high affinity for the p53R175H peptide-HLA complex but does not bind to its wild-type counterpart.

They fused H2 with an antibody fragment that binds to the T cell receptor-CD3 complex on the surface of T cells to convert H2 into a T cell-based immunotherapeutic agent—bispecific single-chain antibody (Bispecific single-chain diabody). This bispecific antibody binds to the p53R175H peptide-HLA complex [dissociation constant (Kd)=86 nM] higher than the typical affinity of T cell receptors, and redirects T cells to recognize cancer cells expressing this complex .

Although the density of this peptide-HLA complex on the cell surface is very low, as quantitatively determined by mass spectrometry, this bispecific antibody effectively activates T cells to secrete cytokines and kill target cancer cells. This killing depends on the expression of homologous HLA and specific TP53 mutations. This bispecific antibody can also cause the regression of human xenograft tumors in mice, whether starting treatment shortly after tumor transplantation or starting treatment when the tumor is already established.

 

The structure of this H2 antibody fragment and p53R175H polypeptide-HLA complex shows that H2 forms a cage-like structure around the mutant amino acid (His175) and an adjacent amino acid (Arg174). The stability of this cage structure provides a structural basis for H2 to recognize this mutant peptide-HLA complex with a high degree of specificity.

In summary, these authors have developed an antibody-based treatment that targets a new antigen derived from a common TP53 mutation in a highly specific manner. Although the antigen density on the surface of tumor cells is very low, it can effectively activate T cells and lyse tumor cells in vitro and in vivo. In theory, this method can be used to treat cancers that contain other mutations, which are difficult to target with conventional means.

 

(source:internet, reference only)


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