One example of a true antigenic surface marker specific to cancer cells is EGFRvIII, a mutation in the epidermal growth factor receptor (EGFR) found in a variety of different cancers but not in normal cells. This true cancer marker is different from the native EGFR that has served as a target for nonspecific cancer therapy (e.g., Genentech/Roche’s monoclonal antibody Avastin) in those cancers in which EGFR is overexpressed. Discovered about ten years ago, EGFRvIII was originally dismissed by scientists but has shown usefulness as a possible therapeutic target. However, while this receptor is cancer specific, it is not organ specific since it appears in several cancer types.
Another potentially useful cancer-specific marker is TMPRSS2:ERG, the fusion product of the prostate-specific marker TMPRSS2 and the transcription factor ERG. TMPRSS2:ERG levels accurately predict the likelihood that prostate cancer patients will relapse after surgery. However, just half of prostate cancer patients express TMPRSS2:ERG, which does not bode well for using this marker as a screening test or general diagnostic.
So despite increasing knowledge in molecular biology in recent years, discovery of cancer-specific, cell-surface antigens remains a challenge. We know genes mutate inside cancer cells, but the molecular manifestation of these events as surface antigens has largely eluded detection and characterization.
This is not surprising, as cancer cells have evolved numerous escape mechanisms for overcoming not just pharmacologic intervention, but the body’s own defense mechanisms. Masking of tumor-specific antigens (TSAs) by a cell’s native surface antigens, which prevents direct interaction with TSAs, is just one such mechanism. Another is the relatively poor immunogenicity of TSAs compared with neighboring antigens.
The standard approach to discovering new proteins involves explicit knowledge of their existence and the ability to isolate them. Barring a first-in-kind discovery, it is quite unlikely that TSAs will be characterized sufficiently given the current state of technology.
MabCure scientists have developed a technique for generating antibodies against TSAs without a priori knowledge of their location or structures. The key is the classic hybridoma technology that was re-engineered and optimized. The technique, which is still in the early validation stage, has produced specific antibodies against melanoma and ovarian cancers.
While TSAs will require development work before approval and commercialization, they provide the scientific basis for designing numerous products for cancer diagnosis, imaging, and therapy.
Cancer-specific antibodies may help change the molecular diagnosis and treatment of cancer. If produced at reasonable cost, such antibodies may be able to improve sensitivity and specificity for cancer screening and diagnosis as well as monitoring of therapy. Similarly tumor-specific mAbs, when coupled with the appropriate radionuclide, might one day pinpoint micrometastases for diagnostic purposes and/or direct radiotherapy. Finally, studies involving the mAbs and their cancer-cell targets may lead to the discovery and characterization of TSAs, which themselves might be the targets of pharmacologic intervention.