Epidermal growth factor receptor (EGFR) is highly overexpressed in malignant mesothelioma (MM). MAb806 is a novel anti-EGFR antibody that selectively targets a tumor-selective epitope. MAb806-derived antibody drug conjugates (ADCs), ABT-414, ABBV-221 and ABBV-322, may represent a novel therapeutic strategy in MM. EGFR and mAb806 epitope expressions in mesothelioma cell lines were evaluated using an array of binding assays, and the in vitro cell effects of ABT-414 and ABBV-322 were determined. In vivo therapy studies were conducted in mesothelioma xenograft and patient-derived xenograft (PDX) tumor models. We also performed biodistribution and imaging studies to allow the quantitative targeting of MM by mAb806 using a ⁸⁹Zr-labeled immunoconjugate—ch806. A high EGFR expression was present in all mesothelioma cell lines evaluated and mAb806 binding present in all cell lines, except NCIH-2452. ABT-414 and ABBV-322 resulted in significant tumor growth inhibition in MM models with high EGFR and mAb806 epitope expressions. In contrast, in an EGFR-expressing PDX model that was negative for the mAb806 epitope, no growth inhibition was observed. We demonstrated the specific targeting of the mAb806 epitope expressing MM tumors using ⁸⁹Zr-based PET imaging. Our data suggest that targeting EGFR in MM using specific ADCs is a valid therapeutic strategy and supports further investigation of the mAb806 epitope expression as a predictive biomarker.

The vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) are key regulators of blood vessel formation, including in tumors, where their deregulated function can promote the production of aberrant, leaky blood vessels, supporting tumor development. Here we investigated the VEGFR1 ligand VEGF-B, which we demonstrate to be expressed in tumor cells and in tumor stroma and vasculature across a range of tumor types. We examined the anti-VEGF-B-specific monoclonal antibody 2H10 in preclinical xenograft models of breast and colorectal cancer, in comparison with the anti-VEGF-A antibody bevacizumab. Similar to bevacizumab, 2H10 therapy was associated with changes in tumor blood vessels and intra-tumoral diffusion consistent with normalization of the tumor vasculature. Accordingly, treatment resulted in partial inhibition of tumor growth, and significantly improved the response to chemotherapy. Our studies indicate the importance of VEGF-B in tumor growth, and the potential of specific anti-VEGF-B treatment to inhibit tumor development, alone or in combination with established chemotherapies.

Background: The novel anti-HER2 antibody 104 (mAb104) targets a unique tumour-specific epitope, lacks normal tissue binding and can internalise into tumour cells, thus supporting its development into antibody drug conjugates (ADCs). Methods: We now describe the binding properties and preclinical activity of mAb104-ADCs developed through the conjugation of mAb104 via linkers to the anti-microtubule drug maytansoinoid ematansine (DM1-SMCC; DM1), topoisomerase I inhibitor, exatecan derivative (MC-GGFG-DX8951; DX8951) or microtubule disruptor monomethyl auristatin E (MC-vc-PAB-MMAE; MMAE). Results: Mab104-ADCs demonstrate dose-dependent cytotoxicity in vitro. The safety of single-dose mAb104-DX8951 was demonstrated in vivo at doses up to 10 mg/kg. MAb104-ADCs also demonstrated potent and prolonged anti-tumour activity in a range of tumour types with variable HER2 expression. Mab104-DX8951 showed significant responses in trastuzumab-resistant HER2-positive breast cancer, low HER2-expressing cancers, as well as HER2-overexpressing cancers. Conclusion: These findings indicate the potential for tumour-specific targeting of HER2-expressing tumours with mAb104-ADCs.

Introduction: Despite their benefit, current anti-EGFR therapies are limited by narrow efficacy profiles due to dose-limiting toxicities. This phase 2 open-label study evaluated the efficacy and safety of ABT-806, an EGFR-targeting antibody that is tumor specific, in patients with advanced EGFR-expressing tumors including head and neck cancers (H&NC) and squamous cell carcinoma (SCC) of other sites. Methods: Patients with advanced H&NC (cohort A) or SCC of other sites (cohort B) were enrolled in the study. ABT-806 was administered as monotherapy at a dose of 24 mg/kg intravenously using a twice weekly dosing schedule until unacceptable toxicity and/or evidence of disease progression. Adverse events (AEs) were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events v4.0; tumor response was assessed using the Response Evaluation criteria in Solid Tumors v1.1. EGFR status was assessed with mAb806 and EGFRvIII immunohistochemistry and correlated with outcomes. Results: ABT-806 was well tolerated with no grade 3+ treatment-related AEs. Disease stabilization was observed in two patients (14%) and for a median duration of 19.5 weeks. This included one patient from cohort A and one patient from cohort B. Progression-free survival and overall survival was not significantly different between the two cohorts. Conclusions: Although clinical activity was limited in this small, heavily pre-treated, and biomarker-unselected population, ABT-806 demonstrated an excellent safety profile with minimal classical EGFR-related toxicity. These findings support the development of more tumor-specific EGFR antibodies for use, particularly in combinatorial regimens.