Abstract 1543: Discovery of antibodies for ADC therapy from cancer patients who show durable clinical response to checkpoint inhibitors
Authors: Scholz Alexander , Aurellano Jerald , Harbell Michael , Zhang Danhui , O'Connor Samantha , Millare Beatriz , Chu Felix , Fernandez Sheila , Czupalla Cathrin J. , Aydin Iraz , Manning-Bog Amy , Leung Yvonne , Williamson Kevin , Carroll Chantia , Kim Dongkyoon , Chen Xiaomu , Carroll Sean M. , Dhawan Ish , Nguyen Ngan , Thyagarajan Shweta , Whidden Mark , Santo Gregg Espiritu , Haaser Nicole , Cavet Guy , Steinman Lawrence , Serafini Tito A. , Volkmuth Wayne , Benjamin Jonathan , Robinson William H. , Greenberg Norman M. , Emerling Daniel , DeFalco Jeff 
Published: August 2019

Abstract
Successful anti-tumor therapy using antibody-drug conjugates (ADCs) depends, in part, on antibodies that bind tumor selective targets that are subsequently internalized at a high rate into tumor cells. Only a select number of tumor-selective internalizing antibodies have been identified, and this has limited the scope of ADC therapeutic strategies in the clinic. Here we demonstrate, using Atreca’s Immune Repertoire Capture (IRC™) technology, that we can identify tumor selective antibodies that have internalization activity suitable for ADC therapeutics directly from cancer patients showing durable clinical response to checkpoint inhibitors. To identify anti-tumor antibodies with hallmarks suitable for ADC applications, we used IRC™ to analyze blood plasmablasts, a type of antibody secreting activated B cell collected from patients with non-progressing metastatic cancer. Antibodies representing expanded clonal families were expressed recombinantly and analyzed for binding to human tumor and non-tumor tissues, as well as for internalization activity using a pH-sensitive dye and cancer cell lines. Those antibodies with a high internalization rate were subsequently tested for in vitro ADC activity using a secondary antibody conjugated with the auristatin MMAE.
We identified multiple patient-derived antibodies, from several cancer types, that bound to human tumor tissue, but not adjacent normal tissue. Of these, several also showed internalization into human A549 lung tumor cells when measured through the detection of a pH-sensitive dye. When used in combination with a secondary antibody conjugated to the MMAE cytotoxic agent, internalizing antibodies were able to induce target cell death in vitro.
In this study, we used Atreca’s IRC™ platform to identify patient-derived antibodies that bind to tumor-selective antigens and a subset that also internalize into cancer cells. Furthermore, we demonstrate that the internalizing antibodies were able to deliver a cytotoxic payload to induce tumor cell death. Overall, we show that the antibody repertoires of cancer patients contain tumor-selective antibodies with potent internalization properties and strong ADC therapeutic potential.
Citation Format: Alexander Scholz, Jerald Aurellano, Michael Harbell, Danhui Zhang, Samantha O'Connor, Beatriz Millare, Felix Chu, Sheila Fernandez, Cathrin J. Czupalla, Iraz Aydin, Amy Manning-Bog, Yvonne Leung, Kevin Williamson, Chantia Carroll, Dongkyoon Kim, Xiaomu Chen, Sean M. Carroll, Ish Dhawan, Ngan Nguyen, Shweta Thyagarajan, Mark Whidden, Gregg Espiritu Santo, Nicole Haaser, Guy Cavet, Lawrence Steinman, Tito A. Serafini, Wayne Volkmuth, Jonathan Benjamin, William H. Robinson, Norman M. Greenberg, Daniel Emerling, Jeff DeFalco. Discovery of antibodies for ADC therapy from cancer patients who show durable clinical response to checkpoint inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1543.