RE: Preclinical Development of PNT6555, a Boronic Acid–Based, Fibroblast Activation Protein-α (FAP)–AP-Positive Tumors17 Feb 2024 16:57
@gmcc, interesting find, thanks. Quick takeaway …
3 (chemically) different FAP targeting ligands (PNT6555, 6952, 6522) with 3 different radioisotopes (177Lu, 225Ac, 161Tb) plus target imaging (PETi) via 68Ga. Complicated, and suggestion that different solutions for different tumour stages.
Work done on mice, some with FAP enhanced tumours. While supportive of “advancement of PNT6555 to the “FAPi Radioligand Open-Label, Phase 1 Study to Evaluate Safety, Tolerability and Dosimetry of [Lu-177]-PNT6555 ... (ClinicalTrials.gov identifier NCT05432193).”, it seems like there’s still a lot of pre-clinical work to do. Needs a very careful read through (please DYOR etc.).
A few general points (no pun intended) re RadioLigandTherapy (RLT) …
Firstly, RLT is not straitforward. Radioisotopes are not inert – you can’t turn radioactivity off (unlike AVA6000 where Doxorubicin is rendered inert until FAP triggered cleavage at the TME), so targeting is critical. Not to mention the supply-chain challenges of radioisotopes.
Lily (Point) and Novartis favour 177Lu and 225Ac (161Tb also mentioned in article). 177Lu is produced by Neutron bombardment of 176Lu, or 177Yb - which then decays to 177Lu. 177Lu has a half-life of 6.6 days, so not long to manufacture the Radioligand. 177Lu decays via beta emission (3 energy levels) and gamma (1 energy level). The beta decay is the treatment.
Most 225Ac came from the Oak Ridge National Laboratory from (slowly) decaying Thorium – but this source is running out. However, you can always batter 232Th with high-energy protons – just need an accelerator next door. 225Ac has a 10-day half-life and decays via alpha emission (high energy, but very short distance, so needs precise targeting).
Lot of work going on working out how to ‘do targeting’ with Radioligands. For example, from Lily (Point) PNT2002 (PSMA), PNT2003 (SSTR - somatostatin receptor) and PNT2004 (FAP).
While there seems to be some progress with PSMA targeting for Prostrate cancer, this mostly involves the use of 68Ga (half-life 68 min) to ‘image’ (via PET) the treatment site, rather than direct targeting.
PNT2003 (collaboration with Lantheus) has just received an ‘abbreviated new drug application (ANDA)’ from the FDA
https://www.cancernetwork.com/view/fda-accepts-abbreviated-nda-for-177lu-pnt2003-in-sstr-gep-nets
Lily (Point) are trying direct PSMA targeting with their PNT2002 ‘splash’ trial (rPFS up from 6 to 9.5 months, though apparently not as good as anticipated, or Novartis’ Pluvicto?) and PNT2001 – which looks like a replacement (already?) for PNT2002. Of course they also now have canSEEK™ (aka pre|CISION™), let’s see where this goes.
In the meantime, we should just ‘get on’ with the AVA6000 trial and ‘accelerate’ the ‘opportunities’ presented by the overall pre|CISION™ platform.
GLA
Sign In
Follow the stocks
