eNews October 12, 2011

Monoclonal antibodies (mAbs) target intracellular oncoproteins in mice

Every once in a while, conventional wisdom is overturned. A refreshing example is the finding that intracellular cancer-specific proteins can be targeted to treat or prevent cancer. In 2011, a research team led by Dr. Qi Zeng from the Institute of Molecular and Cell Biology and the Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, reported successfully using intracellular oncoprotein-specific monoclonal antibodies (mAbs) to markedly retard cancer growth and metastasis in mice (Guo et al. 2011). Previously, mAbs were thought to be too large to pass through cell membranes. Dr. Zeng's and her team's success may lead to a new arsenal of therapies in the fight against cancer and bring us closer to the goal of personalized medicine.

Dr. Zeng's team found that intracellular oncoprotein-specific mAbs could potentially be used to fight cancer in two ways – as therapies against established cancers and as vaccines to slow or prevent cancer development:

  • Female mice hemizygous for the MMTV-PyVT transgene develop palpable mammary tumors by as early as five weeks of age. They are excellent models for studying metastatic human breast cancer.
    mAbs against phosphatase of regenerating liver 3 (PRL-3), an intracellular protein up-regulated in many advanced human cancers, retard the growth and metastases of PRL-3-expressing xenograft tumors in syngeneic C57BL/6 mice.
  • PRL-3 mAbs do not confer cancer resistance in B cell-deficient B6.129S2-Ighmtm1Cgn/J (muMT, 002288) mice, indicating that their cancer-fighting efficacy depends on mature, functional B cells.
  • mAbs against the intracellular polyomavirus middle T (PyVT) antigen markedly retard the growth and metastasis of spontaneous mammary tumors in FVB/N-Tg(MMTV-PyVT)634Mul/J (002374) mice.
  • Targeting intracellular oncoproteins via antibody therapies requires specific antibody-antigen interactions (non-specific antibodies have no effect).
  • Immunizations with purified PRL-3 or mT proteins (antigens) induce immune responses, including the production of antibodies against the antigens, and can be effective vaccines against cancers that express them in mice.

In summary, Dr. Zeng and her colleagues demonstrated that either antibody or antigen-induced antibody (vaccine) therapies against intracellular oncoproteins can significantly arrest tumor progression in mice. Although the mechanisms by which this occurs are unknown, they are most effective in the presence of mature, functional B cells. The ability of mAbs to target intracellular oncoproteins, which were previously thought to be un-targetable, may considerably increase the number and efficacy of individualized cancer therapies and vaccines.