Abstract 669: Development of MGD007, a gpA33 x CD3 bi-specific DART for T-cell immunotherapy of metastatic colorectal cancer
Authors: Moore Paul A. , Alderson Ralph , Shah Kalpana , Yang Yinhua , Burke Steve , Li Hua , Ciccarone Valentine , Bonvini Ezio , Johnson Syd 
Published: May 2015

Abstract
Introduction: Encouraging clinical responses have been observed through various strategies designed to harness T-cells for their anti-tumor properties, including immune checkpoint inhibition, chimeric antigen receptor-expressing T-cells or bispecific molecules designed to co-engage T-cells and cancer cells. Furthermore, a positive correlation has been observed in colorectal cancer between the degree and type of T-cell infiltration and prognosis suggesting that T-cell recruitment strategies may be particularly advantageous in this type of cancer. We have developed MGD007, a Dual-Affinity Re-Targeting (DART®) protein designed to redirect T-cells to target gpA33 expressing colon cancer. MGD007 has enhanced pharmacokinetic properties via incorporation of a neonatal FcR-binding Fc domain. The gpA33 target was selected based on its ubiquitous expression in colorectal cancer including reactivity with putative cancer stem cell populations (Li 2013, AACR #3763). To enable preclinical toxicokinetics and dose optimization, MGD007 was designed to cross-react with non-human primates. Methods: MGD007 was stably expressed in CHO cells and purified to homogeneity via a standard antibody-purification platform; in vitro functional studies were performed with a range of colorectal cancer cell lines and primary human T-cells; tumor growth inhibition studies were performed in NOD-SCID mice co-implanted with Colo205 and human T-cells (1:1 E:T ratio) and treated IV with MGD007; pharmacokinetic analyses were performed in cynomolgus monkeys. Results: MGD007 displays the anticipated bispecific binding properties and mediates potent lysis of gpA33-positive - but not gpA33-negative cancer cell lines through recruitment of either human or cynomolgus monkey T-cells. Concomitant with CTL activity, both T-cell activation and expansion are observed in a gpA33-dependent manner. No cytokine activation was observed with human PBMC alone, consistent with the absence of gpA33 expression on peripheral blood cell populations. Both CD8 and CD4 T-cells mediated lysis of gpA33-expressing tumor cells, with activity accompanied by increases in granzyme levels. Xenograft studies showed tumor growth inhibition at doses as low as 4ug/kg. In cynomologus monkeys, 4 weekly doses of 200ug/kg were well tolerated, with prolonged PK consistent with that of an Fc-containing molecule. Conclusions: MGD007 displays potent activity against colorectal cancer cells consistent with a mechanism of action endowed in its design. Furthermore it displays favorable PK in cynomolgus monkeys supporting convenient dosing. Taken together, these data support further investigation of MGD007 as a potential novel therapeutic treatment for colorectal cancer.
Citation Format: Paul A. Moore, Ralph Alderson, Kalpana Shah, Yinhua Yang, Steve Burke, Hua Li, Valentine Ciccarone, Ezio Bonvini, Syd Johnson. Development of MGD007, a gpA33 x CD3 bi-specific DART for T-cell immunotherapy of metastatic colorectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 669. doi:10.1158/1538-7445.AM2014-669