Abstract
Background: Fibroblast activation protein (FAP) has received increasing attention as an oncological target because of its prominent expression in solid tumors but virtual absence from healthy tissues. Most radioligand therapies (RLT) targeting FAP, however, suffer from inadequate tumor retention or clearance from healthy tissues. Herein we report a FAP-targeted RLT comprised of a FAP6 ligand conjugated to DOTA and an albumin-binder (4-p-iodophenylbutyric acid, IP) for enhanced pharmacokinetics. We evaluated the performance of the resulting FAP6-IP-DOTA conjugate in four tumor models, three of which expressed FAP only on cancer-associated fibroblasts (CAFs) i.e., analogous to human tumors. Methods: Single-cell RNA-seq data were analyzed from 34 human breast, ovarian, colorectal, and lung cancers to quantify FAP-overexpressing cells. FAP6-DOTA conjugates were synthesized with or without an albumin-binder (IP) and investigated for binding to human FAP-expressing cells. Accumulation of 111In- or 177Lu-labeled conjugates in KB, HT29, U87MG, and 4T1 murine tumors were also assessed by radioimaging and/or biodistribution analyses. Radiotherapeutic potency was quantitated by measuring tumor volumes versus time. Results: Approximately 5% of all cells in human tumors overexpressed FAP (CAFs comprised ~77% of this FAP-positive subpopulation, while ~2% were cancer cells). FAP6 conjugates bound to FAP-expressing cells with high affinity (Kd ~1 nM). 177Lu-FAP6-IP-DOTA achieved 88-fold higher tumor dose than 177Lu-FAP6-DOTA and improved all tumor-to-healthy organ ratios. Single doses of 177Lu-FAP6-IP-DOTA suppressed tumor growth by ~45% in all tested tumor models without causing reproducible toxicities. Conclusion: We conclude that 177Lu-FAP6-IP-DOTA constitutes a promising candidate for FAP-targeted RLT of solid tumors.
- Animal Imaging
- Radionuclide Therapy
- Radiopharmaceuticals
- FAP
- Radioligand therapy
- albumin-binder
- cancer-associated fibroblast
- scRNA-seq
- Copyright © 2022 by the Society of Nuclear Medicine and Molecular Imaging, Inc.