Peptide drug improvement using vitamin B 12 and Haptocorrin binding substrate conjugates

12090,208

17/558920

December 22, 2021

The invention involves the coupling of compounds that can be bound by Haptocorrin (R-binder; Transcobalamin I; HC) to a target drug to improve pharmacokinetics, avoid undesirable side effects, and/or modify CNS access and localization. The pharmaceutical effect may be improved by conjugating the drug to haptocorrin binding substrate. This allows the conjugate to become bound to unsaturated haptocorrin in the blood, thereby protecting the drug from metabolism or excretion to increase protein half-life while not interfering with the efficacy of the protein drug. The conjugation may additionally prevent the drug from reaching the central nervous system or modify where the drug localizes and produces undesirable side effects such as nausea or hypophagia. Such a route also would prevent, in all case save for actual vitamin B12, binding by serum transcobalamin II (TCII), and thus not cause B12 deficiency with long term use.

Doyle, Robert (Manlius, NY, US)

SYRACUSE UNIVERSITY (Syracuse, NY, US)

1. A method of providing an improvement to a pharmaceutical effect of a peptide drug, comprising the step of conjugating the peptide drug to an amount of cobinamide so that the peptide drug conjugated to the amount of cobinamide will bind to haptocorrin but not transcobalamin II in serum in the presence of B 12 .

2. The method of claim 1 , wherein the peptide drug is Exendin-4.

3. The method of claim 1 , wherein the improvement comprises a longer half-life when injected intravenously or subcutaneously.

4. The method of claim 1 , wherein the improvement comprises a reduction in central nervous system side effects.

5. The method of claim 4 , wherein the reduction in central nervous system side effects is a reduction in nausea.

6. The method of claim 1 , wherein the improvement comprises a reduction in weight loss associated with the peptide drug.

7. A compound having improved pharmaceutical effect, comprising a peptide drug and a cobinamide bound to the peptide drug, wherein the cobinamide will bind to haptocorrin but not transcobalamin II in serum in the presence of B 12 .

8. The compound of claim 7 , wherein the peptide drug is Exendin-4.

9. The compound of claim 7 , wherein the improvement comprises a longer half-life when injected intravenously or subcutaneously.

10. The compound of claim 7 , wherein the improvement comprises a reduction in central nervous system side effects associated with the peptide drug.

11. The compound of claim 10 , wherein the reduction in central nervous system side effects is a reduction in nausea.

12. The compound of claim 7 , wherein the improvement comprises a reduction in weight loss associated with the peptide drug.

11207415 December 2021 Doyle
20130344620 December 2013 O'Farrell
WO-2006009874 January 2006

Hippe et al. “Nature of vitamin B12 binding: II. Steric orientation of vitamin B12 on binding and number of combining sites of human intrinsic factor and the transcobalamins”, Biochimica et Biophysica Acta (BBA)—Protein Structure vol. 243, Issue 1, Jul. 25, 1971, pp. 75-82 (Year: 1971). cited by examiner
Borner et al., “Corrination of a GLP-1 Receptor Agonist for Glycemic Control without Emesis”, Cell Reports, 2020, 25 pages. (Year: 2020). cited by examiner
Hippe et al., “Nature of Vitamin B12 Binding, II: Steric Orientation of Vitamin B12 on Binding and Number of Combining Sites of Human Intrinsic Factor and the Transcobalamins”, Biochimica Et Biophysica Acta, 1971, 75-82. (Year: 1971). cited by examiner

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