571P - Preclinical evaluation of FAP-2286, a peptide-targeted radionuclide therapy (PTRT) to fibroblast activation protein alpha (FAP)

Background

FAP is a membrane bound protease that has limited expression in normal adult tissues but is highly expressed on cancer associated fibroblasts (CAFs), which are abundant in most tumours. FAP-2286 is a conjugate of a FAP-binding peptide coupled to a radionuclide chelator (DOTA) for use as a potential PTRT for imaging and therapeutic applications. The potency, selectivity, and efficacy of FAP-2286 were evaluated in vitro and in vivo.

Methods

Immunohistochemistry was performed using FFPE tissue specimens. FAP-2286 and its metal complexes were evaluated in in vitro biochemical and cellular assays and in vivo biodistribution, imaging, and efficacy studies.

Results

Immunohistochemistry confirmed high levels of FAP expression, predominantly in CAFs, in multiple tumour types including pancreatic, breast, and sarcoma. In contrast, FAP expression in normal tissues was limited. FAP-2286 and its metal complexes had potent affinity to human FAP protein (K_D, 0.4–1.4 nM). In cellular assays, FAP-2286 showed effective binding (IC₅₀, 1.65–3.4 nM) to FAP expressing WI-38 fibroblasts. FAP-2286 inhibited FAP protease activity (IC_50, 1.6–3.2 nM), whereas limited off target activity was seen against closely related family members. In vivo biodistribution (by SPECT/CT) in mice after IV injection showed rapid uptake of ¹¹¹In- and ¹⁷⁷Lu-labelled FAP-2286 in FAP-positive tumours that was maintained for ≥120 hours, limited background in normal tissues, and a renal clearance mechanism. FAP-2286 labelled with the therapeutic β-particle emitting radionuclide ¹⁷⁷Lu, at a specific activity of 30 MBq/nmol (low-dose group) or 60 MBq/nmol (high-dose group), had potent anti-tumour activity in FAP expressing HEK-293 xenografts after a single IV dose: tumour growth inhibition at day 14 posttreatment was 112% and 115%, respectively, with no significant weight loss.

Conclusions

In preclinical models, FAP-2286 has a compelling profile for PTRT, including high tumour uptake and retention, and potent efficacy in FAP-positive tumours. IND-enabling nonclinical work is ongoing; clinical studies in a broad spectrum of FAP-positive cancers are planned.

Clinical trial identification

Editorial acknowledgement

Editorial support funded by Clovis Oncology was provided by Frederique H. Evans, MBS, of Ashfield Healthcare Communications.

Legal entity responsible for the study

Clovis Oncology, Inc., 3B Pharmaceuticals GmbH.

Funding

Clovis Oncology, Inc., 3B Pharmaceuticals GmbH.

Disclosure

D. Zboralski: Shareholder/Stockholder/Stock options, Full/Part-time employment: 3B Pharmaceuticals GmbH. F. Osterkamp: Shareholder/Stockholder/Stock options, Full/Part-time employment: 3B Pharmaceuticals GmbH . A.D. Simmons: Shareholder/Stockholder/Stock options, Full/Part-time employment: Clovis Oncology. A. Bredenbeck: Shareholder/Stockholder/Stock options, Full/Part-time employment: 3B Pharmaceuticals GmbH. A. Schumann: Shareholder/Stockholder/Stock options, Full/Part-time employment: 3B Pharmaceuticals GmbH. M. Paschke: Shareholder/Stockholder/Stock options, Full/Part-time employment: 3B Pharmaceuticals GmbH . M. Nguyen: Shareholder/Stockholder/Stock options, Full/Part-time employment: Clovis Oncology. J. Xiao: Shareholder/Stockholder/Stock options, Full/Part-time employment: Clovis Oncology. T.C. Harding: Shareholder/Stockholder/Stock options, Full/Part-time employment: Clovis Oncology. A. Hoehne: Shareholder/Stockholder/Stock options, Full/Part-time employment: 3B Pharmaceuticals GmbH. U. Reineke: Shareholder/Stockholder/Stock options, Full/Part-time employment: 3B Pharmaceuticals GmbH. C. Smerling: Shareholder/Stockholder/Stock options, Full/Part-time employment: 3B Pharmaceuticals GmbH . All other authors have declared no conflicts of interest.