US 2004/0110681 A1 · Method to identify targeting molecules

Abstract

Methods for validating the in vivo targeting specificity of compounds according to pharmacokinetic criteria are described. An improved method to generate a library of peptides with reduced complexity and enhanced candidate compound membership comprises expressing oligonucleotides encoding cyclic peptides with randomized coding sequences representing the non-bridging amino acids. Also described is determination of structure activity relationships using kinetic technique using in vivo panning. Design of targeting compounds with appropriate space/charge/hydrophobicity conformations can be based on the results of these kinetic structure activity relationship (kSAR) determinations. In addition, compositions resulting from this methodology are useful in treating neuroinflammatory and lung disorders, and disorders involving disseminated blood cell coagulopathy interactions with vascular endothelium.

Claims57

Dependent claims

A method to validate the ability of a compound to target selectively an organ or tissue which method comprises assessing a pharmacokinetic profile of the compound in a model mammalian or avian subject in vivo wherein said pharmacokinetic profile comprises:

(a) a selectivity index (SI) with respect to a non-targeting molecule;
(b) a specificity index (SPI) with respect to other organs or blood;
(c) a comparison of clearance rate from said tissue or organ as compared to clearance rate from blood using a ratio of areas under the curve and
(d) clearance rate from blood relative to the clearance rate from the target organ, as compared to the behavior of a non-targeting molecule where the clearance rates from blood and the target organ are similar and optionally
(e) dose responsiveness wherein SI is assessed as a function of increasing dose;
according to the parameters
(a′) the SI is >5
(b′) the SPI is >5
(c′) the clearance rate from said tissue or organ as compared to clearance rate from blood has a ratio of areas under the curve of >5
(d′) faster clearance rate from blood than from the tissue or organ in comparison with the behavior of a non-targeting molecule,
(e′) SI is increased with increasing dose,
whereby a compound which satisfies any three of the parameters (a′)-(d′) is validated as having said ability.

9 more elements

Dependencies are inferred from the claim text.

Method to identify targeting molecules

Life of this patent

Method to identify targeting molecules

Life of this patent

Abstract

Claims57