Abstract IA-13: Molecularly targeted imaging and treatment via the integrin αvβ6

Abstract

Abstract The integrin αvβ6 is an epithelial-specific cell surface receptor that is generally undetectable in healthy adult epithelium but is significantly up-regulated in a wide range of epithelial derived cancers including almost 100% of pancreatic cancers. The low expression of αvβ6 in healthy tissue, the high αvβ6 expression in pancreatic cancer cells, and the correlation of expression with the metastatic phenotype of cancer support αvβ6 as a particularly attractive molecular target for both detection and treatment. We previously developed an αvβ6-targeted molecular imaging agent, 18F-αvβ6-binding-peptide (18F- αvβ6-BP), a peptide that has high affinity (nM) and selectivity for the integrin αvβ6 with favorable pharmacokinetics in tumor-bearing mice and non-human-primates, and translated this imaging agent into a first-in-human study in patients with breast, colon, lung and pancreatic cancer (NCT03164486/ IND #124336). The 18F-αvβ6-BP was well tolerated, with PET images demonstrating significant uptake of [18F]αvβ6-BP in both the primary lesion and metastases, including sub centimeter lesions in liver and lung. Building upon these data we have now developed the theranostics pair [68Ga]Ga αvβ6-BP (for detection) and [177Lu]Lu DOTA-ABM- αvβ6-BP (for treatment). Both constructs have demonstrated high affinity (low nM) and selectivity for the integrin αvβ6 both in vitro in cell binding assays and in vivo in mouse models, are rapidly internalized and are stable in both mouse and human serum. The [68Ga]Ga αvβ6-BP and [177Lu]Lu DOTA-ABM αvβ6-BP constructs showed favorable pharmacokinetics in pre-clinical studies, with predominantly renal excretion and good tumor: normal tissue ratios. The [177Lu]Lu DOTA-ABM αvβ6-BP was well tolerated in mice at over 50X the human equivalent dose. In a pre-clinical therapeutic efficacy study, mice in the control groups had met the end point by 69 days from start of treatment. In contrast, the mice in the treatment group had 100% survival at the end of the study i.e. at 120 days. The dosimetry values [177Lu]Lu DOTA-ABM αvβ6-BP extrapolated from the biodistribution data indicated the kidneys and the stomach are the dose limiting organs with the extrapolated values being significantly lower than the federal guidelines for human safety. In a single dose, 14-day GLP acute toxicology study with doses exceeding 100x the human equivalent dose no test article-related effects. We now propose a first-in-human pilot trial for the theranostic pair [68Ga]Ga αvβ6-BP and [177Lu]Lu DOTA-ABM αvβ6-BP in patients with locally advanced or metastatic pancreatic adenocarcinoma (PDAC). In this presentation I will described the design and development of both the diagnostic and the therapeutic constructs, their preclinical evaluation and describe the future plans for the first-in-human pilot trial for the theranostic pair. Citation Format: Julie L. Sutcliffe. Molecularly targeted imaging and treatment via the integrin αvβ6 [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr IA-13.