CYSTINE KNOT PEPTIDES THAT BIND ALPHA-V-BETA-6 INTEGRIN

摘要

Disclosed are peptides comprising a molecular scaffold portion and a loop portion that binds to integrin αvβ6. This integrin is expressed on pancreatic tumors, making the peptides useful as imaging agents, among other uses. The peptides showed single-digit nanomolar dissociation constants similar to antibodies used clinically for imaging and therapy. The peptides rapidly accumulated in αvβ6-positive tumors, which led to excellent tumor-to-normal contrast. The peptides are specific for the targeted integrin αvβ6 receptors expressed on orthotopic pancreatic tumors and various xenografts used. Additionally, pharmacokinetic-stabilization strategies endowed knots with rapid renal clearance, which significantly reduced off-target dosing.

主权项

1. A peptide having specific binding to alpha-V beta 6 integrin, comprising a binding portion between two cysteine residues and a scaffold portion, said peptide being at least 83% identical to a sequence selected from the group consisting of:(SEQ ID NO: 2)(a) (R01),GCILNMRTDLGTLLFRCRRDSDCPGACICRGNGYCG,(SEQ ID NO: 3)(b) (R02),GCRSLARTDLDHLRGRCRRDSDCPGACICRGNGYCG,(SEQ ID NO: 4)(c) (E02),GCRSLARTDLDHLRGRCEEDSDCLAECICEENGFCG,(SEQ ID NO: 5)(d) (S02),GCRSLARTDLDHLRDRCSSDSDCLAECICLENGFCG.(SEQ ID NO: 63)(e) (MΔR),GCILNRRTDLGTLLFRCRRDSDCPGACICRGNGYCG,(SEQ ID NO: 64)(f) (MΔG),GCILNGRTDLGTLLFRCRRDSDCPGACICRGNGYCG,and(SEQ ID NO: 65)(g) (MΔW),GCILNWRTDLGTLLFRCRRDSDCPGACICRGNGYCG.