Integrin-targeting protein and methods of use thereof
Inventors
Liu, Zhi-Ren • Turaga, Chakra Ravi • Yang, Jenny
Assignees
Georgia State University Research Foundation Inc • Proda Biotech LLC
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Publication Number
US-12655197-B2
Publication Date
2026-06-16
Expiration Date
Abstract
A non-toxic anti-angiogenesis protein that inhibits tumor growth and exhibits in vitro activity in induction of angiogenic endothelial cell apoptosis without targeting VEGF/VEGFR or any other RTK pathways is described. The protein targets integrins αvβ3, at a groove in the βA domain of β3 formed by α2 helix, B—C loop, and α2-α3 loop.
Core Innovation
The invention relates to ProAgio, a non-toxic anti-angiogenic/anti-fibrotic polypeptide comprising a variant of domain 1 of cell adhesion protein (D1-CD2) having the amino acid of SEQ ID NO: 4. The polypeptide specifically binds integrin αvβ3 at a βA domain in the region of the β1 helix, B–C loop and β1–β3 loop, with a dissociation constant of less than about 1 μM, including embodiments with values from 10−8 to 10−9 M.
ProAgio includes defined amino-acid substitutions, exemplified by L94N, E95D, K96V, I97C, F98N, D99F, L100A, K101S, and I102R. Cross-linking evidence indicates interaction with integrin αv/α13 at cross-linking sites including TEMKQER (SEQ ID NO:1) and FNEEVKKQ (SEQ ID NO:2), and optional PEGylation is described, including PEG-20 kDa ProAgio-PEG and PEGylated ProAgio-PEG formats.
Mechanistically, ProAgio induces apoptosis in integrin αvβ3-expressing endothelial cells by recruitment and activation of caspase 8 to the β3 cytoplasmic domain. The polypeptide inactivates FAK and disrupts focal adhesion and stress fibers without inducing anoikis, with functional outcomes including disrupted endothelial tube formation, reduced tumor vessel density (CD31), and regression of fibrosis in liver and other cancer-associated fibrosis models.
Therapeutic application is described for cancers and fibrosis, including liver fibrosis, pancreatic fibrosis, and breast cancer associated fibrosis. The document contrasts observed effects relative to AVASTIN/ENDOSTAR and includes reductions in TIMP1 with increased MMP2, plus apoptosis of activated hepatic stellate cells (hHSCs) and activated liver sinusoidal endothelial cells (LSEC). The invention also describes pharmaceutical compositions and administration routes for the polypeptide.
Claims Coverage
The partial content includes two independent claims (clm-00001 and clm-00009). Each claim centers on administering a therapeutically effective polypeptide or pharmaceutical composition based on a D1-CD2 domain 1 variant (SEQ ID NO: 4) that binds integrin αvβ3 at a βA domain region defined by specific structural loops.
Decreasing excessive accumulation of fibrous material by integrin αvβ3 βA domain binding D1-CD2 variant
A method of decreasing excessive accumulation of fibrous material within the extracellular matrix in injured or damaged tissue by administering a polypeptide comprising a variant of domain 1 of cell adhesion protein (D1-CD2) having the amino acid of SEQ ID NO: 4, wherein the polypeptide specifically binds integrin αvβ3 at the βA domain in the region of β1 helix, B–C loop and β1–β3 loop, and wherein the method decreases excessive accumulation of fibrous material in subjects having liver fibrosis, pancreatic fibrosis, or breast cancer associated fibrosis, excluding cases not due to retrolental fibroplasia, idiopathic pulmonary fibrosis, neurofibroma or angiofibroma.
Inducing apoptosis by therapeutically effective D1-CD2 variant binding integrin αvβ3 with K_D < 1 μM
A method of inducing apoptosis in tissue of a subject by administering a therapeutically effective amount of a pharmaceutical composition of a polypeptide that binds specifically to integrins αvβ3, comprising a variant of domain 1 of cell adhesion protein (D1-CD2) having the amino acid of SEQ ID NO: 4, wherein the polypeptide specifically binds integrin αvβ3 at the βA domain in the region of β1 helix, B–C loop and β1–β3 loop, and wherein the polypeptide has a dissociation constant less than 1 μM, with excess accumulation of fibrous material not due to retrolental fibroplasia, idiopathic pulmonary fibrosis, neurofibroma or angiofibroma, and the subject having liver fibrosis, pancreatic fibrosis or breast cancer associated fibrosis.
Across the independent claims, the core claimed coverage is directed to administering a D1-CD2 domain 1 variant (SEQ ID NO: 4) that specifically binds integrin αvβ3 at the βA domain region defined by the β1 helix, B–C loop, and β1–β3 loop, with an additional binding-affinity constraint (K_D < 1 μM) for apoptosis induction, and with targeted fibrosis and cancer-associated fibrosis indications excluding specific alternative causes.
Stated Advantages
Decreases excessive accumulation of fibrous material in injured or damaged tissue within the extracellular matrix.
Induces apoptosis in tissue of a subject.
Excludes subjects where excess accumulation of fibrous material is due to retrolental fibroplasia, idiopathic pulmonary fibrosis, neurofibroma or angiofibroma.
Documented Applications
Treatment of liver fibrosis, pancreatic fibrosis, or breast cancer associated fibrosis by decreasing excessive accumulation of fibrous material within the extracellular matrix.
Inducing apoptosis in tissue of a subject with liver fibrosis, pancreatic fibrosis, or breast cancer associated fibrosis.
Application in a mammal subject.
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