Preclinical Development of PNT6555, a Boronic Acid-Based, Fibroblast Activation Protein-α (FAP)-Targeted Radiotheranostic for Imaging and Treatment of FAP-Positive Tumors.

Autor:	Poplawski SE; Department of Developmental, Molecular and Chemical Biology, Tufts University Graduate School of Biomedical Sciences, Boston, Massachusetts., Hallett RM; POINT Biopharma Global Inc., Indianapolis, Indiana., Dornan MH; POINT Biopharma Global Inc., Indianapolis, Indiana., Novakowski KE; POINT Biopharma Global Inc., Indianapolis, Indiana., Pan S; Department of Developmental, Molecular and Chemical Biology, Tufts University Graduate School of Biomedical Sciences, Boston, Massachusetts., Belanger AP; Harvard Medical School, Boston, Massachusetts.; Molecular Cancer Imaging Facility, Dana-Farber Cancer Institute, Boston, Massachusetts; and., Nguyen QD; Harvard Medical School, Boston, Massachusetts.; Lurie Family Imaging Center, Dana-Farber Cancer Institute, Boston, Massachusetts., Wu W; Department of Developmental, Molecular and Chemical Biology, Tufts University Graduate School of Biomedical Sciences, Boston, Massachusetts., Felten AE; POINT Biopharma Global Inc., Indianapolis, Indiana., Liu Y; Department of Developmental, Molecular and Chemical Biology, Tufts University Graduate School of Biomedical Sciences, Boston, Massachusetts., Ahn SH; Harvard Medical School, Boston, Massachusetts.; Molecular Cancer Imaging Facility, Dana-Farber Cancer Institute, Boston, Massachusetts; and., Hergott VS; POINT Biopharma Global Inc., Indianapolis, Indiana., Jones B; Department of Developmental, Molecular and Chemical Biology, Tufts University Graduate School of Biomedical Sciences, Boston, Massachusetts., Lai JH; Department of Developmental, Molecular and Chemical Biology, Tufts University Graduate School of Biomedical Sciences, Boston, Massachusetts., McCann JAB; POINT Biopharma Global Inc., Indianapolis, Indiana., Bachovchin WW; Department of Developmental, Molecular and Chemical Biology, Tufts University Graduate School of Biomedical Sciences, Boston, Massachusetts; william.bachovchin@tufts.edu.
Jazyk:	angličtina
Zdroj:	Journal of nuclear medicine : official publication, Society of Nuclear Medicine [J Nucl Med] 2024 Jan 02; Vol. 65 (1), pp. 100-108. Date of Electronic Publication: 2024 Jan 02.
DOI:	10.2967/jnumed.123.266345
Abstrakt:	The overexpression of fibroblast activation protein-α (FAP) in solid cancers relative to levels in normal tissues has led to its recognition as a target for delivering agents directly to tumors. Radiolabeled quinoline-based FAP ligands have established clinical feasibility for tumor imaging, but their therapeutic potential is limited due to suboptimal tumor retention, which has prompted the search for alternative pharmacophores. One such pharmacophore is the boronic acid derivative N -(pyridine-4-carbonyl)-d-Ala-boroPro, a potent and selective FAP inhibitor (FAPI). In this study, the diagnostic and therapeutic (theranostic) potential of N -(pyridine-4-carbonyl)-d-Ala-boroPro-based metal-chelating DOTA-FAPIs was evaluated. Methods: Three DOTA - FAPIs, PNT6555, PNT6952, and PNT6522, were synthesized and characterized with respect to potency and selectivity toward soluble and cell membrane FAP; cellular uptake of the Lu-chelated analogs; biodistribution and pharmacokinetics in mice xenografted with human embryonic kidney cell-derived tumors expressing mouse FAP; the diagnostic potential of ⁶⁸ Ga-chelated DOTA-FAPIs by direct organ assay and small-animal PET; the antitumor activity of ¹⁷⁷ Lu-, ²²⁵ Ac-, or ¹⁶¹ Tb-chelated analogs using human embryonic kidney cell-derived tumors expressing mouse FAP; and the tumor-selective delivery of ¹⁷⁷ Lu-chelated DOTA-FAPIs via direct organ assay and SPECT. Results: DOTA-FAPIs and their ^nat Ga and ^nat Lu chelates exhibited potent inhibition of human and mouse sources of FAP and greatly reduced activity toward closely related prolyl endopeptidase and dipeptidyl peptidase 4. ⁶⁸ Ga-PNT6555 and ⁶⁸ Ga-PNT6952 showed rapid renal clearance and continuous accumulation in tumors, resulting in tumor-selective exposure at 60 min after administration. ¹⁷⁷ Lu-PNT6555 was distinguished from ¹⁷⁷ Lu-PNT6952 and ¹⁷⁷ Lu-PNT6522 by significantly higher tumor accumulation over 168 h. In therapeutic studies, all 3 ¹⁷⁷ Lu-DOTA-FAPIs exhibited significant antitumor activity at well-tolerated doses, with ¹⁷⁷ Lu-PNT6555 producing the greatest tumor growth delay and animal survival. ²²⁵ Ac-PNT6555 and ¹⁶¹ Tb-PNT6555 were similarly efficacious, producing 80% and 100% survival at optimal doses, respectively. Conclusion: PNT6555 has potential for clinical translation as a theranostic agent in FAP-positive cancer. (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)
Databáze:	MEDLINE
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