Ann: SABRE topline results, page-41

I agree that these SABRE results are exceptional and that Cu64-SAR-Bombesin has great potential as a diagnostic, but I'm not as convinced about the use of Cu67 as a therapeutic, mainly due to my concerns re off-site toxicity. Many diverse cells in the body produce GPR as a functional neuropeptide involved in many physiological processes in the healthy individual. Equally, many diverse cells express the receptor site. These receptor sites will bind Bombesin almost as well as the intrinsic GR peptide and so all should "light up" when exposed to Cu64-SAR-Bombesin. Presumably, the diagnostic can differentiate between these healthy tissue cells and the cancerous-expressing cells, maybe due to quantitatively lower binding if the healthy cells are not clustered as would occur in a cancerous growth. All diagnostics have signalling limitations so I presume that they have been able to resolve such background noise as a non sensitivity issue in interpreting the scans.

However, subsequent treatment with Cu67-SAR-Bombesin ( as in combat trial) presumably would also target these healthy GRPR cells, with the radiation dose also killing off limited surrounding cells and thereby adversely affecting normal metabolic signalling. Hence my concern re off site toxicity, and I wonder if this could be an undisclosed factor in Clarity's decision to stop the trial.

I guess the same argument could be made against PSMA, which is also expressed on the surface of various healthy tissues. But the difference is that PSMA is a surface bound cell antigen and not a signalling molecule like GRP neuropeptide. and CU64-SAR-bis-PMSA is not binding to and attacking a cell signalling function.

I asked ChatGPT for any supporting information:

Me: what cells in humans produce Gastrin Releasing Peptide (GRP) and which ones have the receptor (GRPR) for this hormone?

ChatGPT (its bold font):

Gastrin-Releasing Peptide (GRP) is a neuropeptide involved in a variety of physiological processes, especially in the gastrointestinal and nervous systems. Here’s a detailed look at which human cells produce GRP and which express its receptor (GRPR):

Cells That Produce GRP in Humans:

1. Neuroendocrine Cells:

   • Enteric neurons in the gastrointestinal (GI) tract: GRP is primarily produced by neurons of the enteric nervous system (especially in the stomach and duodenum).

   • Pulmonary neuroendocrine cells (PNECs): Found in the lungs; these cells release GRP during lung development and in response to injury or disease.

   • Hypothalamic neurons: GRP is also synthesized in certain regions of the hypothalamus, involved in neuroendocrine regulation.

2. Neuroendocrine Tumors:

   • Certain small cell lung carcinomas and other neuroendocrine tumors produce ectopic GRP, often as part of a paraneoplastic syndrome.

Cells That Express GRPR (Gastrin-Releasing Peptide Receptor):

1. Gastrointestinal Tract:

   • Smooth muscle cells and epithelial cells in the stomach and intestines express GRPR, mediating effects like gastric acid secretion, smooth muscle contraction, and motility.

2. Central Nervous System (CNS):

   • Neurons in the hypothalamus, amygdala, and spinal cord: GRPR is involved in regulating circadian rhythms, fear memory, and itch sensation.

   • In particular, spinal cord dorsal horn neurons express GRPR, playing a major role in itch (pruritus) transmission.

3. Prostate and Breast Tissue:

   • GRPR is expressed in some prostate and breast epithelial cells and is upregulated in certain cancers, making it a target for imaging and therapy.

4. Lung Tissue:

   • Bronchial epithelial cells and smooth muscle cells express GRPR, which may be involved in inflammatory responses and lung development.

Summary Table

	Tissue/Organ	GRP Production	GRPR Expression
1	GI Tract	Enteric neurons	Epithelial & smooth muscle cells
2	Lung	Pulmonary neuroendocrine cells (PNECs)	Bronchial epithelial cells, smooth muscle
3	Brain	Hypothalamic neurons	Hypothalamus, amygdala, spinal cord neurons
4	Tumors	Neuroendocrine tumors (e.g., small cell lung carcinoma)	Various tumor cells (e.g., prostate, breast)

Me: Can all these receptor cells bind Bombesin as well as GRP

ChatGPT:

Can GRPR-Expressing Cells Bind Bombesin?

Yes, most cells that express GRPR (Gastrin-Releasing Peptide Receptor) can also bind bombesin, because bombesin is a high-affinity agonist of GRPR.

Background: Bombesin and GRP

• Bombesin is a 14-amino acid peptide originally isolated from frog skin (Bombina species).

• In mammals, GRP is the homolog of bombesin — it binds to the same receptor (GRPR) and mimics many of bombesin's actions.

So, GRP and bombesin both activate GRPR in humans, but bombesin is not naturally produced in humans — it's used experimentally or therapeutically due to its GRPR-binding properties.

Bombesin Binds GRPR With High Affinity

Cells with GRPR:

• Bind both GRP and bombesin.

• Respond to both peptides with similar intracellular signaling (e.g., via Gq-protein–mediated phospholipase C activation, intracellular calcium release, and MAPK signaling).

Thus, bombesin is often used in research and diagnostic imaging to probe GRPR-expressing tumors, such as:

• Prostate cancer

• Breast cancer

• Small cell lung carcinoma

Other Bombesin Receptors (in Humans)

Although GRPR is the primary receptor for GRP and bombesin in humans, there are two additional human bombesin-like peptide receptors:

1. Neuromedin B receptor (NMBR) – binds neuromedin B.

2. Bombesin receptor subtype 3 (BRS-3) – orphan receptor; its endogenous ligand is still uncertain.

Bombesin can weakly bind NMBR and BRS-3 at higher concentrations, but its highest affinity is for GRPR.

✅ Summary

	Receptor	Natural Ligand in Humans	Binds Bombesin?	Cell/Tissue Expression
1	GRPR	GRP	✅ Strong binding	CNS, GI tract, lungs, tumors
2	NMBR	Neuromedin B	⚠️ Weak binding	CNS, peripheral tissues
3	BRS-3	Unknown (orphan)	⚠️ Weak/uncertain	CNS, reproductive tissues

Is this something you have considered? I have not looked in fine detail at these trials so I may have missed prior commentary on this.
Cheers