Abstract 50: HTI-1511, a novel anti-EGFR-ADC, overcomes mutation resistance and demonstrates significant activity against multiple tumor types in preclinical studies
Authors: Bahn Jesse D. , Gao Feng , Huang Lei , Blouw Barbara , Zhao Chunmei , Chen Kelly , Zimmerman Susan , Wise Erin K. , Mancini Maria L. , Bird Matthew , McDowell William , Thompson Curtis B. , Rosengren Sanna , Thanos Christopher D. 
Published: July 2017

Abstract
Multiple solid tumor types over-express epidermal growth factor receptor (EGFR). Antibodies that target the receptor are often accompanied by adverse skin reactions due to interaction with receptors expressed in normal tissue. Additionally, downstream mutations (KRAS, BRAF) within tumors can result in EGFR-independent activation and resistance to treatment. We have previously described HTI-1511, an antibody-drug conjugate in pre-clinical development that targets EGFR. HTI-1511 carries the potent cytotoxin MMAE and a novel bis-alkylating linker, connected to a monoclonal antibody engineered to have improved specificity for EGFR in the tumor microenvironment (Huang et. al. AACR National Meeting, 2016, New Orleans, LA). Here we screened a panel of over 70 tumor cell lines derived from various solid tumor malignancies for both EGFR expression by flow cytometry and sensitivity to cell growth inhibition by HTI-1511 in vitro. Cell lines derived from head and neck squamous cell carcinoma (SCC15, CAL27, FaDu, CAL33, SCC25 [IC50 0.52 nM - 3.1 nM]), non-small cell lung cancer (HCC827, NCI-H1666, PC-9, NCI-H1650 [IC50 0.04 nM - 6.2 nM]), and pancreatic carcinoma (BxPC-3, PANC-1, AsPC-1 [IC50 0.99 nM - 4.44 nM]) showed particular sensitivity to HTI-1511. In conjunction, HTI-1511 efficacy was assessed in vivo for tumor growth inhibition (TGI) in several human tumor xenograft models. Evaluations in the human xenografts A431 (epidermoid, 93% TGI at 3.0 mg/kg, p&lt;0.05), BxPC3 (pancreatic, &gt;100% TGI at 3.0 mg/kg, p&lt;0.05), AsPC-1 (pancreatic, &gt;100% TGI at 3.0 mg/kg, p&lt;0.05), and FaDu (HNSCC, &gt;100% TGI at 3.0 mg/kg, p&lt;0.05) indicated dose dependent tumor regressions in all cases, and no observed toxicity when administered weekly at dose levels up to 3 mg/kg for up to eight weeks. HTI-1511 anti-tumor activity was also investigated in a group of patient derived xenograft (PDX) models. An initial study evaluated weekly administration of a single dose level of 2.5 mg/kg HTI-1511 in three different PDX models. TGI of 83% (p&lt;0.05) was observed in a BRAFmut colorectal cancer model and 57% (p&lt;0.05) in a wildtype colorectal cancer model, as well as 46% (not significant) TGI seen in a wild type renal cell carcinoma model. A separate study in a NSCLC (KRASmut) PDX model demonstrated a dose dependent response with greater than 100% TGI at 1.0 and 3.0 mg/kg (both p&lt;0.05, and also p&lt;0.05 to a non-cognate antibody ADC control). The non-cognate antibody control yielded 67.4% (not significant) TGI by itself compared to the vehicle control group. These results support further development of HTI-1511 as a possible treatment for EGFR overexpressing tumors, including those with downstream activating mutations in the KRAS/BRAF pathway.
Citation Format: Jesse D. Bahn, Feng Gao, Lei Huang, Barbara Blouw, Chunmei Zhao, Kelly Chen, Susan Zimmerman, Erin K. Wise, Maria L. Mancini, Matthew Bird, William McDowell, Curtis B. Thompson, Sanna Rosengren, Christopher D. Thanos. HTI-1511, a novel anti-EGFR-ADC, overcomes mutation resistance and demonstrates significant activity against multiple tumor types in preclinical studies [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 50. doi:10.1158/1538-7445.AM2017-50