Can monoclonal antibodies target oncoproteins directly in the cancer cell?
This week a fascinating paper appeared in one of my favorite journals, Science Translational Medicine. Until now, it had been assumed that antibodies only bind to proteins found on the cancer cell surface, largely because of the size of the molecules:
“Because antibodies are viewed as too large to access intracellular locations, antibody therapy has traditionally targeted extracellular or secreted proteins expressed by cancer cells.”
Not so fast!
Guo et al., (2011) have now demonstrated that proteins hidden within cells can be attacked by antibodies as well.
This paper is first to report that antibodies can actually directly target intracellular oncoproteins such PRL-3 that reside within cancer cells, thereby suppressing cancer growth:
“As proofs of concept, we selected three representative intracellular proteins as immunogens for tumor vaccine studies: PRL-3 (phosphatase of regenerating liver 3), a cancer-associated phosphatase; EGFP (enhanced green fluorescent protein), a general reporter; and mT (polyomavirus middle T), the polyomavirus middle T oncoprotein.
A variety of tumors that expressed these intracellular proteins were clearly inhibited by their respective exogenous antibodies or by antigen-induced host antibodies (vaccination).”
In plain English, the data clearly showed that the antibodies induced tumour regression in mice.
What fascinated me was that the tumour regression depended on the presence of immune B cells, which are responsible for antibody production, potentially by improving entry of the antibodies into the tumor cell. Vaccination with the intracellular proteins spurred production of specific antibodies by the host, which also led to tumour regression.
What are the potential mechanisms involved in the therapeutic antibody effect?
Guo et al., (2011) suggested several possibilities:
- A small fraction of intracellular antigens may be released due to necrosis or cancer cell lysis.
- Some intracellular antigens may be externalized and displayed on the surface of cancer cells by unconventional secretion.
- Binding of antibodies to surface-exposed intracellular proteins may then trigger immune responses such as ADCC to destroy the cancer cells.
- Antibodies could be taken up by the cancer cells in an antigen-specific manner.
- Complement-mediated events may also be involved.
In other words, it could be highly complex with several factors involved. These will no doubt be studied further to elucidate the mechanisms more precisely.
What are the implications of this research?
Remember – tumours targeted with unrelated antibodies usually produce no beneficial response – which was also seen in this research.
Overall, I think if the concept of targeting targeting intracellular oncoproteins with antibody therapy or vaccination were to be reproducible in human research, then new, highly specific cancer targets may well emerge in clinical trials, much in the same way the HER2 protein was used as a highly specific target for a subset of breast cancer patients.
In order to have higher response rates from cancer therapeutics, we need to have better, more specific targets than we currently see in the clinic. I’ll be following this development to see where it goes, whether new translational research and also specific monoclonal antibodies will emerge, as a result of these findings from the basic research.
It might take a little while, but that would be great news for cancer patients.
References:
Guo, K., Li, J., Tang, J., Tan, C., Hong, C., Al-Aidaroos, A., Varghese, L., Huang, C., & Zeng, Q. (2011). Targeting Intracellular Oncoproteins with Antibody Therapy or Vaccination Science Translational Medicine, 3 (99), 99-99 DOI: 10.1126/scitranslmed.3002296
2 Responses to “Can monoclonal antibodies target oncoproteins directly in the cancer cell?”
I dont have access to this journal but the proposed mechanisms shown here rely on the fact that the proteins are intracellular but could be also expressed as surface molecules. If this is true, then the mAbs are not targeting intracelular proteins, they are targeting membrane proteins that are also inside the cell, and this is well known for other cancer therapy target proteins.
This would be easy to check by bioinformatics approaches that guess if proteins are stable when membrane bound. It would be also easy to know if these proteins are expressed on the membrane of tumor cells arising in those mice by simple flow cytometry.
Other possible mechanism would be that tumor cells internalize the mAbs, upon binding to Fc receptors for example, and once inside the cell they could bind the targets. Whatever, the lack of mechanism seems to be a problem under this papers surprising title.
Good points – I would be most interested to see any bioinformatics data that might evolve in this area. It would seem that the authors are working on the mechanism, so hopefully this will evolve soon.
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