202P - Mining tumor infiltrating B cells to discover antibody-target pairs and develop novel therapies

Background

Tumor-infiltrating B cells (TIB) and especially B cells organized in tertiary lymphoid structures (TLS) correlate with better prognosis in lung cancer patients. B cells in the TLS were found to express typical markers of late-stage maturation, somatic hypermutation and class switch recombination of immunoglobulin genes, indicating a cancer-driven clonal expansion. In some cases, research showed that secreted immunoglobulins of the repertoire were having a direct tumor killing activity.

Methods

To decipher and then harness the potential of these tumor-trained antibodies, we analyze recombinant cognate repertoires of tumor infiltrating B cells from lung cancer surgical resections. We leverage the capabilities of Dropzylla®, a cutting-edge single-cell microfluidic platform, to extract and clone the comprehensive B cell antibody repertoire from up to a million tumor-derived B cells. The recombinant antibody repertoires are then screened in a panel of assays designed to identify antibodies with anti-tumor properties. For instance, identification of antibodies showing specific binding to cancer cells. Once identified, the monoclonal antibody is then used to deconvolute novel tumor associated antigens.

Results

The antibodies obtained from lung cancer resections bearing TLS were analyzed by next generation sequencing (NGS). It revealed that a typical sample of approximately one cubic centimeter of tumor tissue yielded thousands of antibody families. The sequences show signs of affinity maturation and clonal expansion which may indicate an antigen-driven B cell development induced by the tumor microenvironment. Some of the tumor derived monoclonal antibodies do bind to cancer cell lines but not healthy cells. Some show direct tumor cell growth inhibition and others promote NK cell mediated killing of cancer cells.

Conclusions

Tumor derived antibodies can bind to shared tumor associated antigens and can have direct anti-tumor activities. We are currently evaluating the targets of the antibodies. These promising results may lead us to discover novel pathways to be exploited as therapy and contribute to further understanding B cells biology in cancer.

Legal entity responsible for the study

Memo Therapeutics AG.

Funding

Memo Therapeutics AG.

Disclosure

M. Delince: Financial Interests, Personal, Full or part-time Employment: Memo Therapeutics AG.