A patient derived antibody targeting the tetraspanin CD9 inhibits tumor progression and metastasis
Wouter Pos1, Remko Schotte1, Els Verdegaal2, Julien Villaudy1, Daniel Go1, Christien Fatmawati1, Camille Bru1, Pauline van Helden1, Sjoerd van der Burg2, Hergen Spits1
1AIMM Therapeutics, Amsterdam, The Netherlands
2Department of Clinical Oncology, Leiden University Medical Center (LUMC), Leiden, The Netherlands
It is generally accepted that immune reactions against cancer cells can be induced by immunotherapy. Here, we investigated the possibility that an antibody response has contributed to the success of the immunotherapy of a cancer patient.
A patient with metastatic melanoma was successfully treated by adoptive transfer of ex vivo expanded autologous tumor reactive T cells1. This patient is still tumor free 10 years after treatment and has developed both CD4 and CD8 neoantigen-reactive T cells2,3. Peripheral blood memory B cells were immortalized by forced Bcl-6 and Bcl-xL expression4 and analyzed for the presence of tumor-reactive B cells.
We isolated a B cell clone that produced an antibody, named AT1412, recognizing a novel cell surface epitope on the tetraspanin CD9. CD9 is widely expressed and involved in multiple cellular activities including proliferation and adherence. AT1412 shows minimal reactivity to various healthy tissues and did not induce aggregation of platelets. In contrast, AT1412 showed significant stronger binding to melanoma cells compared to melanocytes indicating that the AT1412 epitope is overexpressed on tumor cells. In addition, AT1412 strongly reacted with other tumor types including colon, pancreas and breast cancer. Further analysis revealed that AT1412 favors binding to a clustered state of CD9. These clusters are dependent on palmitoylation of CD9 and known to be enhanced on metastatic cells5. We observed that AT1412 blocks tumor progression as a single agent but more strongly in combination with anti PD1 using immunodeficient mice having a human immune system. AT1412 strongly stimulated influx of macrophages and of CD8+ T cells into the tumor. Furthermore, we observed that the antibody strongly inhibited formation of metastases.
These data suggest that the antibody contributed to the success of the immunotherapy in this patient. The antibody could provide help to tumor-reactive T cells in the eradication of circulating tumor cells and/or settlement of metastatic tumor cells in vivo. Of note, no antibody-related adverse effects were observed during and after treatment of this patient indicating that the antibody is safe for use in humans.
- Verdegaal et al, Cancer Immunol Immunother, 2011
- Linneman et al, Nature Med, 2014
- Verdegaal et al, Nature, 2016
- Kwakkenbos et al, Nat Med, 2010
- Yang, JBC, 2006