P2.06-10 ABT-806 Derived Antibody Drug Conjugates (ADCs) Inhibit Growth of Malignant Mesothelioma In-Vivo

Abstract

Malignant mesothelioma (MM) is an aggressive malignancy of the pleura with limited therapeutic options, and is associated with a poor prognosis. EGFR is known to be highly over-expressed in mesothelioma with reported EGFR overexpression between 44 to 97%. We have investigated an anti-EGFR antibody (ABT-806), which is tumour specific and robustly inhibits EGFR-expressing tumors. We have previously shown that ABT-806 ADCs demonstrate potent anti-tumor activity in 806 immunohistochemistry (IHC) positive MSTO-211H MM cell line xenograft model. We present data in MM using ABT-806 novel ADCs [ABT-414 (ABT-806- monomethyl auristatin F), ABBV-221 (ABT-806- monomethyl auristatin E), ABBV-322 (ABT-806- pyrrolobenzodiazepine)] and ABBV-321 (Affinity-matured ABT-806- pyrrolobenzodiazepine) in MM patient derived xenografts (PDX). We evaluated expression of EGFR and mAb 806 IHC in MM cell lines and PDXs. PDXs were implanted into 5 to 10 NOD-Scid mice per group and treated with control ADC, saline, cisplatin or ABT-806 ADCs and followed longitudinally with caliper measurements. Comparative statistics were performed in Graphpad prism. Quantitative biodistribution and imaging of mAb806 uptake (89Zr-ch806) were performed to allow correlation of mAb806 concentration in MM tumours. Three PDX models were selected according to their 806 IHC statuses (2 epithelioid 806 IHC positive, 1 biphasic histology 806 IHC negative). In one epithelioid PDX model, ABBV-322 resulted in significantly reduced tumor growth on day 27 post therapy with median tumour volumes of 180 mm3 (ADC control) compared with 78mm3 (ABBV-322; p=0.0159 two-sided). Moreover, the median survival was also significantly longer in ABBV-322 treated models (p=0.018). In the other epithelioid PDX model, ABBV-321 also resulted in significant responses (median 428mm3 (ADC control) vs 167mm3 (ABBV-321, p= 0.0201) [Figure 1]. In the 806 IHC negative PDX model, the differences in tumor volumes between all groups were found to be non-statistically significant (ADC control vs ABT-414, ADC control vs ABBV-221, ADC-control vs ABBV-321 groups) with p=0.0597 for one-way ANOVA. MSTO211H cell line xenograft model also demonstrated significant anti-tumour response to both ABT-414 and ABBV-221 (p<0.01). Whole-body PET/MR images also confirmed localization of 89Zr-Ch806 to the established MSTO-211H xenograft tumours. In a disease with limited therapies, ABT-806 targeting ADCs in MM demonstrated significant responses in 806+ PDX and cell lines. These data support clinical expansion of these compounds in 806+ MM patients.