In several clinical trials, antibody company Micromet has demonstrated outstanding efficacy and safety of its bispecific BiTE antibodies which come with two binding sites: one for a cancer target and a second one for a T cell. As a result, T cells are recruited and guided directly to the tumor cell, initiating cancer cell death in a serial fashion.
In this week’s PNAS, researchers of the company demonstrate that the BiTE antibodies also can overcome the notorious resistance against conventional monoclonal antibodies arising in many cancer patients.
The researchers converted the anti-EGFR antibodies cetuximab (Erbitux) and panitumumab (Vectibix) into BiTE antibodies by adding the binding site for T cells. In animal models, these BiTE antibodies then showed a remarkably high potency (in the sub-picomolar range) against cancer cells with KRAS and BRAF-mutations which made them resistant to the original monoclonal antibodies.
According to the authors, “the present study shows that conversion of EGFR-specific monoclonal antibodies cetuximab and panitumumab into T cell-engaging BiTE antibodies is technically feasible and that the BiTE technology can overcome resistance of KRAS- and BRAF- mutated CRC lines to the therapeutically used parental antibodies. The simplest explanation for the latter is that T cell-engaging BiTE antibodies do not rely on inhibition of EGFR signaling but use the receptor tyrosine kinase as mere surface anchor for attachment of cytotoxic T cells. This function of BiTE antibodies is not expected to be affected by mutations of downstream components of the EGFR pathway that obviate the cancer cell’s dependence on the EGFR surface receptor for delivery of growth-promoting signaling.”
If this holds up in clinical trials, it is not only good news for patients with resistance to conventional cancer antibodies already on the market, but it will also provide an opportunity for a whole range of new cooperations with pharma companies for product enhancement and life cycle management.