By using antibodies targeting fragments of the p53 protein presented by the major histocompatibility complex, researchers have made a previously ‘undruggable’ intracellular protein more accessible.

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Turning immunotherapy inside out

31 Aug 2020

A novel targeting strategy may make pave the way for effective cancer immunotherapy against previously ‘undruggable’ targets.

Like the guided missiles used in military warfare, precision technology is also used in the field of cancer immunotherapy—antibodies that selectively bind to and destroy cancer cells reduce collateral damage and provide a vast improvement over conventional chemotherapy.

Designing such antibodies, however, remains a challenge as mutated protein targets are frequently intracellular and inaccessible to antibodies. One such key target is p53, an intracellular protein that is mutated in about half of all cancers.

Instead of targeting mutant p53 directly, researchers led by Cheng-I Wang, a Principal Investigator at A*STAR’s Singapore Immunology Network (SIgN), decided to exploit a useful feature found in cells—proteins are continually degraded into peptide fragments and displayed on the cell surface by class I molecules of the major histocompatibility complex (MHC).

While peptide-MHCs containing mutant p53 sequences are rare due to MHC-binding restrictions, elevated levels of peptide-MHCs presenting wild-type p53 peptides can potentially differentiate cancer cells from healthy cells.

“Elevated levels of these peptide-MHC complexes in cancer cells is a good surface marker that differentiates cancer cells from healthy cells, which have low basal levels of similar complexes. These peptide-MHC complexes are thus attractive targets for targeted therapy,” explained Lionel Low and Angeline Goh, SIgN researchers and co-first authors of the study.

By screening over a thousand human antibody fragments for their binding affinity to wild-type p53 peptide-MHCs, the researchers identified an antibody clone, P1C1, which displayed strong binding affinity and low non-specific binding.

Through affinity maturation, they selected for P1C1TM, a high-affinity binder that accumulated in the tumors of mice expressing mutant p53. It also facilitated antibody-dependent cellular cytotoxicity against mutant p53 expressing-tumor cell lines in vitro.

As a proof of concept to show that P1C1TM can act a drug delivery carrier, the team attached a cytotoxic drug to the antibody and showed that the drug-antibody conjugate inhibited the growth of mutant p53-expressing tumors in a xenograft mouse model.

The research team has filed for a patent covering P1C1TM and is now conducting further research into their antibody technology for potential clinical commercialization.

“Other intracellular proteins can potentially be targeted with the same approach, opening up a whole range of possible therapeutic targets that were previously ‘undruggable,’” Low shared.

The A*STAR-affiliated researchers contributing to this research are from the Singapore Immunology Network (SIgN).

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Low, L., Goh, A., Koh, J., Lim, S., Wang, CI. Targeting mutant p53-expressing tumours with a T cell receptor-like antibody specific for a wild-type antigen. Nature Communications 10 (1), 5382 (2019) | article

About the Researcher

Cheng-I Wang

Principal Investigator

Singapore Immunology Network
Cheng-I Wang received a PhD degree in chemistry from Washington University and completed his postdoctoral training in the department of pharmaceutical chemistry at the University of California, San Francisco. Wang worked on drug discovery projects at biotechnology and pharmaceutical companies in the US before joining the A*STAR Singapore Immunology Network (SIgN) in 2009. As Head of the Human Monoclonal Antibody Technology Platform at SIgN, Wang works on the discovery and development of human antibodies against infection and immune disorders, using combinatorial approaches to incorporate novel functions into protein and antibody molecules.

This article was made for A*STAR Research by Wildtype Media Group