Abstract 42: Preclinical development of a duocarmycin-based antibody-drug conjugate targeting B7-H3 for solid cancer (2017)

Abstract Introduction: B7-H3, a member of the B7 family of immunomodulatory molecules, is overexpressed in a wide range of solid cancers. B7-H3 overexpression has been correlated with disease severity and poor outcome in several cancer types. Proof-of-concept studies targeting B7-H3 demonstrated that auristatin-based B7-H3 antibody-drug conjugates (ADCs) exhibited potent cytotoxicity in vitro and antitumor activity in vivo toward a range of B7-H3-expressing tumor cell lines. Based on these preliminary results, we undertook preclinical development of a B7-H3 ADC comprised of a humanized B7-H3 mAb conjugated to a potent DNA alkylating payload. Methods: Chimeric B7-H3 mAbs were conjugated to vc-seco-DUocarmycin-hydroxyBenzamide Azaindole (DUBA) (ADC conjugated and provided by Synthon Biopharmecuticals B.V). In vitro and in vivo activity studies were conducted with tumor cell lines that overexpress B7-H3. Based on the potency analysis, together with the biophysical properties and immunohistochemistry (IHC) profiles of the candidates, a lead mAb was selected for preclinical development. The mAb was humanized via CDR grafting and conjugated to DUBA to yield the development candidate MGC018. In vitro and in vivo studies were then conducted with MGC018 to confirm and extend the results with the chimeric ADCs. Results: Confirming our previous data and consistent with a growing body of literature, B7-H3 mAbs exhibited strong reactivity toward carcinoma cells and the vasculature of solid cancers. Chimeric B7-H3-DUBA ADCs demonstrated specific, dose-dependent cytotoxicity toward B7-H3-positive tumor cell lines in vitro and potent antitumor activity in vivo. The humanized ADC development candidate, MGC018, retained the favorable biophysical properties and the normal tissue-versus-tumor IHC profile of the parental mAb. MGC018 displayed cytotoxicity toward B7-H3-positive tumor cell lines in vitro, with IC50 values in the sub-nM range, and potent antitumor activity in vivo, resulting in tumor stasis and tumor regression in mice bearing B7-H3-positive human tumor xenografts, representing breast, lung and ovarian cancers. Conclusion: MGC018, a preclinical candidate comprised of a humanized mAb targeting B7-H3 conjugated to the potent DNA alkylating payload DUBA via a cleavable peptide linker, exhibited a favorable preclinical profile, with strong reactivity toward tumor cells and tumor-associated vasculature, limited normal tissue reactivity, potent cytotoxicity in vitro and antitumor activity in vivo toward a range of B7-H3-expressing tumor cell lines representing several cancer types. Our findings support further preclinical development of MGC018 to evaluate its potential as an ADC therapeutic for B7-H3-expressing solid cancers. Citation Format: Thomas Son, Juniper A. Scribner, Jeff Hooley, Michael Chiechi, Pam Li, Timothy E. Hotaling, Anushka De Costa, Yan Chen, Francine Chen, Bhaswati Barat, Valentina Ciccarone, Timur Gaynutdinov, James Tamura, Scott Koenig, Syd Johnson, Paul A. Moore, Ezio Bonvini, Deryk Loo. Preclinical development of a duocarmycin-based antibody-drug conjugate targeting B7-H3 for solid cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 42. doi:10.1158/1538-7445.AM2017-42