Promising phase 1 trial…

[Jpburns]

Kinda an overly-optimistic press release here, but look forward to this sort of therapy becoming a reality. If I’m grasping it correctly, it uses the same sort of technology as PSMA to target PC cells with radiological agents.

mdpile.com/news/breakthroug...

Also, how’s this different from Pluvicto?

“Pluvicto is a theranostic treatment — an approach that uses specially designed molecules to first find and bind to specific biomarkers on cancer cells, wherever they might be, and then enter the tumour cell. Radioisotopes attached to the molecules then deliver radiation directly into the cancer cells, damaging the DNA inside and killing them.”

[GP24]

Ac225 has more severe side effects than Pluvicto. It very often causes dry mouth. I would not join this trial.

[Maxone73]

Check this out: Cu-67 SAR-bisPSMA the first guy treated with two doses had a complete response

[spencoid2]

I hate these overly optimistic reports with no technical details. Actinium is an alpha emitter so has higher activity but shorter reach. The idea is that higher doses of isotope can be delivered more precisely. However the big problem with current (don't know about this one because they give few details) Actinium treatment is the limited specificity of the ligand. It attaches to saliva glands and can permanently damage them. It looks like this new treatment uses a different ligand FL-020 this is discussed in another article by the manufacturer and it sort of suggests that it might be more psma specific than other ligands but this article is also vague.

225Ac-FL-020 is a novel PSMA-targeting radionuclide drug conjugate (RDC) with superior in vivo anti-tumor activity

F. Liu1, J. Zhang1, J. Yang1, K. T. Thrane2, M. W. Hallund2, R. V. Grønlund2, N. C. L. Wong1;

1Full-Life Technologies Limited, 2Minerva Imaging ApS, Ølstykke, Denmark

Fa Liu, Ph.D.

Full-Life Technologies Limited

Email: [e-mail]

Website: full-life.com

⚫ 111In-FL-020 and 177Lu-FL-020 displayed a very promising in

vivo distribution profile with high and sustained tumor uptake and fast

systemic clearance.

⚫ 225Ac-FL-020 exhibited superior anti-tumor activity compared to 225Ac-

PSMA-617 at the same dose level (10 KBq/mouse) in the LNCaP

xenograft model with a favorable safety profile as indicated by body

weight and hematological parameters.

⚫ 225Ac-FL-020-treated LNCaP tumor samples where DNA double-strand

breaks and tumor cell apoptosis were observed, confirming the MOA of

alpha emitters.

⚫ Taken together, these results collectively demonstrate that 225Ac-FL-020

is a potent and selective PSMA-targeting radioligand therapy candidate

with superior anti-tumor activity and a favorable safety profile that will

be investigated in a Phase I clinical trial in 2024.

Despite significant developments over the last few decades,

metastatic castration-resistant prostate cancer (mCRPC)

remains incurable. Prostate specific membrane antigen

(PSMA), directly correlates with androgen independence,

metastasis, and disease progression. PSMA has been well-

established as a radioligand target for the diagnosis and

treatment of mCRPC1. Lutetium (177Lu) vipivotide

tetraxetan (Pluvicto®) was approved in 2022 for the

treatment of progressive PSMA-positive mCRPC2. However,

only 30% of patients showed a radiological response in the

registrational trial together with a grade1/2 xerostomia in

around 39% of patients3. These data request for further

improvement in the clinical benefit and toxicity profile of

PSMA-targeted radiotherapy. Actinium-225 (225Ac), an alpha

emitter, demonstrated potent cancer cell killing and a

shorter range in tissue penetration when compared to the

beta emitter 177Lu4, 5. This profile supports the development

of 225Ac based radiotherapies. Using our proprietary Clear-

XTM technology platform, we developed 225Ac-FL-020, a

novel 225Ac-based PSMA radioligand therapy candidate

[lokibear0803 in reply to spencoid2]

But don’t salivary glands express PSMA also? i.e. being more PSMA-specific wouldn’t help us here with off-target effects, am I thinking straight? Maybe that’s not what you’re saying.

[spencoid2 in reply to lokibear0803]

not sure but i thought that the ligand used with the new thing FL-020 was more specific not just psma?

[lokibear0803 in reply to spencoid2]

The only takeaways from the article seems to be:

225Ac-FL-020 … aims to improve drug uptake in tumors while ensuring fast systemic clearance

…225Ac-FL-020 represents a significant advancement

…quickly eliminated by the body, reducing potential toxicity…

So that implies the fast systemic clearance is what reduces toxicity. That, uh, seems reasonable. A bit more useful is this (which looks like the same paper as your quote):

aacrjournals.org/cancerres/...

…where (my own paraphrase) off-target screening indicates high selectivity, high tumor uptake, ”superior” anti-tumor activity compared to Ac-PSMA-617, and rapid systemic clearance.

So far, of course, only in mice. I guess Phase 1 will give some insight about humans.

[spencoid2 in reply to lokibear0803]

so maybe it is the fast clearing that would decrease the chance of xerostomia i sort of thought i sw a reference to a different ligand but ???

[lokibear0803 in reply to spencoid2]

I think both are correct; it looks like a different ligand (FL-020 vs e.g. 617), and maybe that’s why there’s faster clearance, which is maybe why less off-target effects,

:dunno:

[j-o-h-n in reply to spencoid2]

Oh spencoid2,

You're starting to scare me.....(are you chilling with my ex?)

Good Luck, Good Health and Good Humor.

j-o-h-n