Abstract 5041: TEM-1 targeted alpha therapeutic [Ac-225]-FPI-1848 induces regression in pre-clinical sarcoma xenograft models
Bibliographic record
Abstract
Abstract 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> SK-N-AS> 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.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.003 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".