Abstract 6530: Old target, but new approach: Targeting cancer-associated MUC1 with ADC and Car-T

Abstract

Purpose: The characteristics of aberrant overexpression and distinct features of cancer-associated (CA)-MUC1 has been often considered as a promising target in most of the solid cancers. MUC1 is composed of α and β subunits to form a full length of MUC1, and α subunit is released and circulated into the blood in cancer, which is used as biomarkers such as CA 15-3 and CA 27-29. As those α subunit-targeting strategies were failed in the numerous clinical trials due to, at least in part, the diminished α subunit of MUC1 in cancer, we have developed a humanized Ab, PAb001 targeting the residual β subunit of MUC1, called as an onco-tethered (OT)-MUC1. To prove the concept of this strategy, an antibody-drug conjugate (ADC) and chimeric antigen receptor (CAR) T cells were applied to assess its efficacies. Methods: We produced a monoclonal antibody (mAb) against OT-MUC1 from mouse and sequentially generated its derivative humanized antibody, PAb001. Then, the target product profiles (TPP) were determined by SPR, ELISA, FACS, immunohistochemical analysis, pilot tissue cross-reactivity, and pharmacokinetics (PK) analysis. Then, to evaluate anti-cancer efficacies, we either conjugated PAb001 with Monomethyl auristatin E (MMAE) or generated the second-generation CAR T cells and then sequentially tested in vitro and in vivo cancer models. Results: Based on the TPP criteria, PAb001 antibody was chosen over a hundred of candidate antibodies tested. Next, it was conjugated with MMAE, treated and measured its cytotoxicity in ovarian and breast cancer cell lines, including triple-negative breast cancers (TNBC). As a result, PAb001-ADC selectively inhibited the growth of cancer cell lines, depending on the expression level of MUC1. Also, it showed 80-100 % tumor growth inhibition rates (TGI) in the cell lines- and patient-derived xenograft models. Lastly, OT-MUC1 Car-T cells showed significant and selective growth inhibition of cancer cells. Conclusion: Taken together, the preclinical studies of PAb001-ADC and Car-T indicate the high therapeutic potentials targeting OT-MUC1 in cancer, which further provided the rationale for clinical development. Citation Format: Jin G Jung, Min-Seok Kim, Hwa-Chul Jung, Hoil Choi, Kyung-Duk Moon. Old target, but new approach: Targeting cancer-associated MUC1 with ADC and Car-T [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6530.

Targeted Drug Delivery Using a Plug-to-Direct Antibody–Nanogel Conjugate

“…Inspired by the results of Trastuzumab-ANCs toward HER2-expressing cancer cells, we tested the applicability of ANCs to target cells with different overexpressed receptors. Specifically, tumor-specific mucin 1 (tMuc1) and epidermal growth factor receptor (EGFR) show great potential in different breast cancer subtypes. , In contrast to tumor tissue, where the tMuc1 epitope is exposed, the Muc1 epitope in healthy tissue is highly glycosylated masking the epitope. , The unique glycosylation status and common appearance in breast cancers (>90%) of mucin 1 proteins are quite appealing for the development of ADCs that specifically target tMuc1. ,, In this work, we conjugated an anti-tMuc1 antibody, TAB004, to the nanogels to target tMuc1-positive breast cancer cells. The choice of cargo was established from an IC50 screening of four commonly used drugs, including DOX, PTX, DM1, and SN38, where SN38 showed the highest sensitivity to both tMuc1 and EGFR-expressing cell lines (Figure S17).…”

“…Specifically, tumor-specific mucin 1 (tMuc1) and epidermal growth factor receptor (EGFR) show great potential in different breast cancer subtypes. 41,42 In contrast to tumor tissue, where the tMuc1 epitope is exposed, the Muc1 epitope in healthy tissue is highly glycosylated masking the epitope. 43,44 The unique glycosylation status and common appearance in breast cancers (>90%) of mucin 1 proteins are quite appealing for the development of ADCs that specifically target tMuc1.…”