Leland Stanford Junior University

Sanofi

Richard H Kimura

Jennifer R Cochran

Sanjiv Sam Gambhir

Aron M Levin

Zhen Cheng

Christian Lange

Jochen Kruip

Ingo Focken

Benjamin Joseph Hackel

Mathias Gebauer

Frederick T Chin

Bin Shen

Arutselvan Natarajan

Susanta K Sarkar

Ohad Ilovich

Robert Teed

Engineered peptides that bind with high affinity (low equilibrium dissociation constant (Kd)) to the cell surface receptors of fibronectin (&#x3b1;&#x3b2;) or vitronectin (&#x3b1;&#x3b2;and &#x3b1;&#x3b2;integrins) are disclosed as useful as imaging tissue. These peptides are based on a molecular scaffold into which a subsequence containing the RGD integrin-binding motif has been inserted. The subsequence (RGD mimic) comprises about 9-13 amino acids, and the RGD contained within the subsequence can be flanked by a variety of amino acids, the sequence of which was determined by sequential rounds of selection (in vitro evolution). The molecular scaffold is preferably based on a knottin, e.g., EETI (Trypsin inhibitor 2 (Trypsin inhibitor II) (EETI-II) [Ecballium elaterium (Jumping cucumber)], AgRP (Agouti-related protein), and Agatoxin IVB, which peptides have a rigidly defined three-dimensional conformation. It is demonstrated that EETI tolerates mutations in other loops and that the present peptides may be used as imaging agents.

Peptides and related compositions and methods

Engineered peptides that bind with high affinity (low equilibrium dissociation constant (Kd)) to the cell surface receptors of fibronectin (&#x3b1;&#x3b2;) or vitronectin (&#x3b1;&#x3b2;and &#x3b1;&#x3b2;integrins) are disclosed as useful as imaging tissue. These peptides are based on a molecular scaffold into which a subsequence containing the RGD integrin-binding motif has been inserted. The subsequence (RGD mimic) comprises about 9-13 amino acids, and the RGD contained within the subsequence can be flanked by a variety of amino acids, the sequence of which was determined by sequential rounds of selection (in vitro evolution). The molecular scaffold is preferably based on a knottin, e.g., EETI (Trypsin inhibitor 2 (Trypsin inhibitor II) (EETI-II) [(Jumping cucumber)], AgRP (Agouti-related protein), and Agatoxin IVB, which peptides have a rigidly defined three-dimensional conformation. It is demonstrated that EETI tolerates mutations in other loops and that the present peptides may be used as imaging agents.

Engineered integrin binding peptide compositions

The invention relates to a companion diagnostic antibody-like binding protein based on the humanized monoclonal antibody, DS6, to be used as diagnostic tool for in vivo detection and quantification of the tumor-associated MUC1-sialoglycotope, CA6.

Immuno imaging agent for use with antibody-drug conjugate therapy

Imaging methods using engineered integrin binding peptides

Disclosed are peptides comprising a molecular scaffold portion and a loop portion that binds to integrin &#x3b1;&#x3b2;. 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 &#x3b1;&#x3b2;-positive tumors, which led to excellent tumor-to-normal contrast. The peptides are specific for the targeted integrin &#x3b1;&#x3b2;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.

Cystine knot peptides that bind alpha-V-beta-6 integrin

Engineered peptides that bind with high affinity (low equilibrium dissociation constant (Kd)) to the cell surface receptors of fibronectin (&#x3b1;&#x3b2;) or vitronectin (&#x3b1;&#x3b2;and &#x3b1;&#x3b2;integrins) are disclosed. These peptides are based on a molecular scaffold into which a subsequence containing the RGD integrin-binding motif has been inserted. The subsequence (RGD mimic) comprises about 9-13 amino acids, and the RGD contained within the subsequence can be flanked by a variety of amino acids, the sequence of which was determined by sequential rounds of selection (in vitro evolution). The molecular scaffold is preferably based on a knottin, e.g., EETI (Trypsin inhibitor 2 (Trypsin inhibitor II) (EETI-II) [(Jumping cucumber)], AgRP (Agouti-related protein), and Agatoxin IVB, which peptides have a rigidly defined three-dimensional conformation. It is demonstrated that EETI tolerates mutations in other loops and that the present peptides may be used as imaging agents.

Engineered integrin binding peptides

Growing community of inventors

Menlo Park, CA, United States of America

Richard H Kimura