Validation of a novel anti-BMP2/4 inhibitor for treatment of Barrett’s esophagus
During the past decades the highly malignant Esophageal adenocarcinoma (EAC) has become an important health burden. Despite intensive treatments including chemo-and radiotherapy, and surgery, 5-year survival is less than 15%. The only way to improve survival is through more effective prevention. Barrett’s esophagus (BE) is a frequently occurring premalignant lesion of the esophagus that predisposes for EAC. At present, effective pharmacological erradication therapies for BE do not exist. Currently patients with BE are under periodic endoscopic surveillance to examine for early malignant changes in order to apply ablative therapies or surgery. These procedures are stressful, invasive and not cost effective.
Our team has studied the molecular mechanisms underlying the development of BE and were able to develop highly specific antibodies, which target a specific signaling pathway involved in the development of BE. In preclinical in vivo studies we were able
to demonstrate that these molecules effectively can inhibit the growth of Barrett cells and sustain development of the normal esophageal cells.
In this project the partnership of the AMC team with the company QvQ will join forces to demonstrate the safety of the molecules and provide more evidence that the cells that develop upon treatment of Barret mucosa are healthy and do not carry mutations. Also, we will humanize the molecules in order to prevent severe adverse events in humans. The outcomes will be a early safety profile and several humanized forms of the antibodies that will be ready for further GMP production and toxicity screening.
Deliverables of the project:
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Previously generated VHH antibodies against BMP2 and BMP4 were characterized further and found to be highly selective for inhibiting BMP2 and BMP4 with an affinity at least as high as Noggin, a known, non-selective BMP inhibitor binding to BMP2/4 but also to all other BMPs.
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Using RNA sequencing and QPCR a biomarker (PXR) was identified that can predict the progression of Barrett’s esophagus to esophagus carcinoma. The expression of this marker was tested with several antibodies on patient biopsy material and QPCR, with QPCR yielding representative values. This marker is relatively new and will need to be validated in independent Barrett’s patient cohorts before it can be used to identify Barrett patients with a high risk of developing cancer and thus are candidates to be treated with our VHHs.
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We succeeded in humanizing the most important VHH (C8C8), however we failed to do so for C4C4.
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In vitro testing in luciferase and cell migration assays indicated that the humanized forms of the VHHs maintained their capacity in inhibiting the BMP2/4 pathway and in inhibiting cell growth and migration.
The VHHs now need to be produced under GMP conditions and tested in animal studies for pharmaco dynamics and pharmaco kinetics for defining toxicity level and determining the dosing levels. Hereto sponsorship and involvement of VC is required. A bottleneck is still that the treatment will be relatively expensive for treating Barrett patients who are relative low risk for developing cancer and therefore it is difficult to find partners who are interested. Developing the drug for cancer treatment may be a better way to pursue.
