In the past thirty years, with the rapid development of molecular biology, scientists have gained a deeper understanding of the pathogenesis of cancer and have continuously developed promising molecular targeted therapeutic drugs for specific cancers. However, due to the unique circumstances of each patient, most targeted therapies are only effective for a small subset of patients. In most cases, there are no known targeted biomarkers for the patient's tumor. Therefore, determining effective personalized treatment methods has always been a huge challenge in this field.

Recent studies have found that cancer patients develop antibody responses to their own tumors, and these anti-tumor antibodies are quite mature in their ability to specifically recognize cancer cells. However, they are not yet sufficient to produce therapeutic effects.

On May 6, 2022, a research team from the University of Pennsylvania published a paper titled: Rapid, site-specific labeling of “off-the-shelf” and native serum autoantibodies with T cell–redirecting domains The research paper.

The research team has come up with a 'crazy idea' - to use cancer patients' own antibodies to discover and treat their own cancer. Based on this idea, the research team has developed a simple method to covalently link T cell redirection domains specifically to any pre-existing human immunoglobulin G (IgG) or naturally isolated IgG from serum, generating bispecific antibodies in just a few hours.

Using this method, the research team constructed T cell redirecting autoantibodies (TRAAb), which can serve as effective anti-cancer drugs that preferentially bind to tumor tissue rather than healthy tissue, and do not require recognition of tumor markers.

By combining the efficacy of the patient's own specific antibodies with bispecific antibodies, the innate ability of the immune system to recognize tumors as foreign substances is utilized to create a truly personalized therapy that is effective for tumors.

Among antibody drugs, monoclonal antibodies are one of the most important categories. However, this treatment method can only target one antigen or one epitope, and the pathogenesis of certain cancers has been found to be related to multiple pathways. In order to target more pathways to enhance anti-tumor efficacy, antibody technology has developed bispecific antibodies.

The concept of bispecific antibodies (bsAb) was first proposed by American immunologist Alfred Nisonoff in 1964. Until 2014, the US FDA approved the first bispecific antibody drug Blincyto (developed by Amgen, CD19 × CD3) for the treatment of relapsed or refractory B-cell acute lymphoblastic leukemia.

In recent years, with an increasing number of encouraging clinical research results, bispecific antibodies have developed into a promising cancer treatment method. It is constructed through genetic recombination, chemical conjugation, or quadruple hybridization, and can simultaneously bind to two independent targets or two different antigenic epitopes on the same target. When used as a therapeutic agent, this has significant implications, such as enhancing specific biological effects.

T cell redirection bispecific antibody is a novel targeted therapy drug that builds a bridge between tumor cells and T cells to enhance the immune clearance ability of cancer cells.

The bispecific antibody drug Blincyto (developed by Anjin Company, CD19 × CD3) is the first T cell redirecting bispecific antibody, which has been proven in previous clinical studies to provide clinical remission of precursor B-cell acute lymphoblastic leukemia at a dose of 1/1000 of rituximab (anti-CD20 monoclonal antibody).

Scientists have previously developed many design formats for bispecific antibodies (bsAB). However, due to the low yield and purity of BsAb prepared by chemical crosslinking technology, as well as limited universality and applicability of species restricted pairing. Therefore, generating high-purity BsAb typically requires extensive antibody engineering or pre cloning, which can take several months at the fastest.

In this latest study, the research team developed a simple method to covalently link the anti-CD3 targeting domain (pAbBD) specifically to the heavy chain of pre-existing human immunoglobulin G (IgG) or naturally isolated IgG from serum. This method of preparing bsAB does not require antibody engineering, cloning, or modification, and can generate bispecific antibodies in just a few hours.

Prior to this, it was impossible to convert natural antibodies into bispecific antibodies.

The research team generated T cell redirecting autoantibodies (TRAAb) by labeling antibodies isolated from tumor bearing mice (including two homologous models). Mouse experiments have shown that antibody domain mediated TRAAB preferentially binds to tumor tissue rather than healthy tissue, making it an effective therapeutic agent without the need to recognize tumor markers.

The research team stated that using autoantibodies to guide bispecific antibody targeting of tumors represents a new paradigm of personalized medicine and eliminates the need to identify tumor biomarkers. Meanwhile, a previously unexplored therapeutic window was also discovered.

The co corresponding author of the paper, Andrew Tsourkas, stated that there is still a lot of work to be done before this study can become a practical clinical therapy. But I hope this can at least inspire new ideas for personalized medicine.

The research team stated that the next steps will focus on separating anti-tumor antibodies from other antibodies found in patient serum (as this may redirect bispecific antibodies to other parts of the body), as well as examining potential therapeutic effects, adverse reactions, and immunogenicity induced by treatment. Overall, this study brings hope for the development of new cancer targeted therapies.

Paper link:

https://www.science.org/doi/10.1126/sciadv.abn4613

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