Abstract 5041: TEM-1 targeted alpha therapeutic [Ac-225]-FPI-1848 induces regression in pre-clinical sarcoma xenograft models
Authors: Collens Sean , Robinson Nicole , Moran Matt , Simms Ryan , Storozhuk Yarina , Hu Meiduo , Grinshtein Natalie , Forbes John , Leamon Christopher P. , Valliant John 
Published: April 2023

Background: Tumor endothelial marker 1 (TEM-1 or CD248) is a cell surface receptor belonging to a family of C-type lectin transmembrane proteins. Identified as a fetal antigen, expression peaks during embryogenesis but is minimally detected in adulthood. In pathological conditions TEM-1 has been shown to be overexpressed in cancer and fibrosis. In sarcomas, expression occurs throughout the tumor environment in malignant cells, stromal cells and perivascular cells. The first line of treatment for sarcomas is surgical removal; however, many sarcomas arise in inoperable sites prompting a need for novel therapies. Herein, we describe the development of a novel TEM-1 targeting radiotherapeutic, [225Ac]-FPI-1848, in mouse xenograft models of sarcoma.

Methods: [225Ac]-FPI-1848 is a radioimmunoconjugate consisting of a humanized anti-TEM-1 monoclonal antibody conjugated to a proprietary DOTA-based chelate (FPI-1397) and radiolabeled with actinium-225 [225Ac]. [177Lu]-FPI-1835 is the lutetium-177 radiolabeled analogue. The biodistribution and therapeutic efficacy of these radioimmunoconjugates were evaluated in human sarcoma xenograft models using nu/nu mice of Balb/c background. For biodistribution studies, approximately 37 MBq/kg of [177Lu]-FPI-1835 was injected intravenously into mice and tumor/organ radioactivity was quantified ex vivo at timepoints between 4 and 196 h. For therapeutic studies, a single intravenous dose of [225Ac]-FPI-1848 was administered over a dose range of 18.5 to 740 kBq/kg. Tumor size and body weight were monitored for 28 days.

Results: Biodistribution studies with [177Lu]-FPI-1835 confirmed robust tumor uptake with minimal normal tissue uptake in three sarcoma models expressing high (SJSA-1), moderate (SK-N-AS) or low (A673) levels of TEM-1. Furthermore, the degree of uptake trended with TEM-1 expression levels across these models (SJSA1&gt; SK-N-AS&gt; A673). In corresponding therapeutic studies, [225Ac]-FPI-1848 demonstrated dose-dependent efficacy consistent with tumor uptake. In the SJSA-1 model, tumor regression was observed at doses of 92.5 kBq/kg or greater. Tumor regression was observed at doses of 185 kBq/kg or greater in the SK-N-AS model. In the low TEM-1 expressing A673 model, significant tumor regression was only observed at the highest radionuclide dose level (740 kBq/kg). Overall, therapy was well tolerated with no significant loss of body weight or clinical signs of poor health.

Conclusions: [177Lu]-FPI-1835 demonstrated target-dependent uptake consistent with the degree of TEM-1 expression in human sarcoma xenograft models. In turn, corresponding efficacy studies with [225Ac]-FPI-1848 demonstrated strong dose-dependent, and target level-dependent efficacy with no apparent toxicity. These results suggest [225Ac]-FPI-1848 could be a promising therapy for TEM-1 expressing sarcomas.

Citation Format: Sean Collens, Nicole Robinson, Matt Moran, Ryan Simms, Yarina Storozhuk, Meiduo Hu, Natalie Grinshtein, John Forbes, Christopher P. Leamon, John Valliant. TEM-1 targeted alpha therapeutic [Ac-225]-FPI-1848 induces regression in pre-clinical sarcoma xenograft models. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5041.