Abstract A145: DS-8201a, a novel HER2-targeting ADC with a novel DNA topoisomerase I inhibitor, demonstrates a potent anti-tumor efficacy with differentiation from T-DM1 in preclinical studies
Authors: Ogitani Yusuke , Yamaguchi Junko , Ishii Chiaki , Hirai Takehiro , Atsumi Ryo , Morita Koji , Hayakawa Ichiro , Naito Hiroyuki , Masuda Takeshi , Nakada Takashi , Jikoh Takahiro 
Published: May 2016

Abstract
Antibody-drug conjugates (ADCs) represent a promising drug class which expresses a wider therapeutic window than conventional chemotherapeutic agents by effecting efficient and specific drug delivery to antigen-expressing tumor cells. DS-8201a is a HER2-targeting ADC structurally composed of a humanized anti-HER2 antibody, enzymatically cleavable peptide-linker, and a novel topoisomerase I inhibitor (DXd), which is cell-membrane permeable and more potent than SN-38 the active metabolite of irinotecan. This ADC achieves a high drug-to-antibody-ratio (DAR, 7 to 8) with homogeneous conjugation with DXd. DS-8201a is cleaved by lysosomal enzymes and releases DXd in the cytoplasm after it binds to HER2 receptors and is internalized in tumor cells.
In order to evaluate the pharmacological potential of DS-8201a, in vitro and in vivo studies were performed in comparison with T-DM1. T-DM1 is a commercialized HER2-targeting ADC with a tubulin polymerization inhibitor that is approved for treatment for HER2-positive breast cancer. In vitro studies indicated that DS-8201a exhibited a HER2 expression-dependent cell growth inhibitory activity. In vivo studies using a HER2-positive gastric cancer NCI-N87 cell line-derived xenograft (CDX) model suggested that DS-8201a induced a dose-dependent tumor growth inhibition and tumor regression with a single dosing at more than 1 mg/kg. In comparison with T-DM1, 1) DS-8201a was effective against T-DM1-insensitive breast and gastric patient-derived xenograft (PDX) models with high HER2 expression. 2) DS-8201a, but not T-DM1, demonstrated anti-tumor efficacy against several breast cancer PDX models with low HER2 expression. 3) DS-8201a showed a complete response in mice inoculated with a mixture of HER2-positive and -negative cells while T-DM1 did not.
These differentiations may be due to the different mechanisms of action of each conjugated drug (topoisomerase I inhibition vs. tubulin polymerization inhibition), higher DAR of DS-8201a (7 to 8 vs. 3.5), and DS-8201a's more potent bystander killing due to higher cell membrane permeability of conjugated toxin.
When taken together with over 30 CDX and PDX models from 8 tumor types (breast, gastric, cholangiocarcinoma, esophagus, colon, NSCLC, pancreas, and ovary) conducted so far, DS-8201a induced tumor regression in over 20 models with various HER2 expression levels though T-DM1 induced regression in only 8 models with high HER2 expression.
In conclusion, these studies suggest that DS-8201a, a novel HER2-targeting ADC, may be more efficacious in a broader patient population than T-DM1, and in tumors which current anti-HER2 therapies are ineffective, such as T-DM1 insensitive tumors and low HER2-expressing tumors, and in tumors with high HER2 heterogeneity. The first in human study will be initiated in 2015 3Q.
Citation Format: Yusuke Ogitani, Junko Yamaguchi, Chiaki Ishii, Takehiro Hirai, Ryo Atsumi, Koji Morita, Ichiro Hayakawa, Hiroyuki Naito, Takeshi Masuda, Takashi Nakada, Takahiro Jikoh. DS-8201a, a novel HER2-targeting ADC with a novel DNA topoisomerase I inhibitor, demonstrates a potent anti-tumor efficacy with differentiation from T-DM1 in preclinical studies. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A145.