Abstract 643: Identification of novel pancreatic cancer-specific antibodies and their target antigens through a next generation immune sequencing platform
Authors: Fabrizio David A. , Timberlake Sonia , Belmont Brian , Goldfless Stephen J. , Briggs Adrian W. , Broering Teresa J. , Vigneault Francois 
Published: August 2015

One of the major challenges in developing new therapies for pancreatic cancer is the lack of known specific and sensitive targets to the cancer cells. In this study, we present a powerful way to identify novel specific targets to pancreatic cancer by leveraging the antibody responses of tumor infiltrating lymphocytes (TILs) using a novel next-generation immune sequencing approach. We first deeply characterize the antibody repertoire produced by TILs, followed by antibody expression, screening and functional characterization to identify their biological targets. We aim to manipulate the antibody cancer targeting specificity into potential therapeutics by utilizing antibody-drug conjugation (ADC) technology.

We obtained tumor resections and matched normal adjacent tissue from patients diagnosed with pancreatic ductal adenocarcinoma or acinar cell carcinoma, and characterized each sample's TIL immune repertoire using AbVitro's proprietary Next-Generation Immune Sequencing platform. Interestingly, results indicated the presence of millions of B and T cells in both tumor and normal tissues. Strikingly, tumor tissues across all patients were characterized by an abundance of expanded B-cell lineages expressing IgG, whereas normal adjacent tissue and healthy control samples contained almost exclusively IgA expressing cells. Antibody candidates were selected from the sequencing data and heavy and light chains were synthesized and expressed in a mammalian cell-based expression system. The antibodies were then screened for cell surface binding, tissue specificity and cell killing potential against pancreatic cancer cell lines and FFPE human cancer tissues. Selected antibodies from these screens were then chosen as candidates for antigen identification.

Our study uncovered multiple antibodies that specifically bind to pancreatic cancer tissues but not to healthy tissues. Interestingly, some of the antibodies also showed strong binding to other types of cancer such as lung squamous cell carcinoma. Initial target identification efforts for these antibodies yielded a short list of antigens which are known to be expressed at high levels in the pancreas or pancreatic cancer cell lines. We are currently performing studies to further understand the antigen specificity and sensitivity of these antibodies and evaluate their cell killing potential as ADCs, as well as investigating the diagnostic value of the novel antigen targets. In summary, our study demonstrates the potential of next-generation sequencing in TIL analysis for the discovery of novel cancer-specific targets of potential therapeutic value.

Citation Format: David A. Fabrizio, Sonia Timberlake, Brian Belmont, Stephen J. Goldfless, Adrian W. Briggs, Teresa J. Broering, Francois Vigneault. Identification of novel pancreatic cancer-specific antibodies and their target antigens through a next generation immune sequencing platform. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 643. doi:10.1158/1538-7445.AM2015-643