Methods and compositions for PDGF-CC inhibition
Inventors
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Assignees
Hamra Invest AB • Paracrine Therapeutics AB
MemberParacrineParacrineParacrine develops regenerative therapies for chronic wound care, leveraging autologous cell-based treatments and real-time AI platforms to enhance healing precision, predictability, and efficiency. The company operates globally, focusing on scalable and cost-effective biological solutions that integrate advanced machine learning for improved patient outcomes.
Paracrine develops regenerative therapies for chronic wound care, leveraging autologous cell-based treatments and real-time AI platforms to enhance healing precision, predictability, and efficiency. The company operates globally, focusing on scalable and cost-effective biological solutions that integrate advanced machine learning for improved patient outcomes.
Publication Number
US-11352420-B2
Publication Date
2022-06-07
Expiration Date
Abstract
The present invention relates, in part, to isolated antibodies that specifically interact with and show measurable binding affinity to an epitope of platelet derived growth factor C (PDGF-C). Such antibodies may be used for the modulation of PDGF-C activity in or secreted from a cell to study its effects on cell function and, in certain embodiments, for the treatment and/or prevention of a disease or condition associated with PDGF-C signing pathway.
Core Innovation
The invention provides isolated antibodies, including murine 6B3, ch6B3, humanized hu6B3 with a preferred R30 heavy-chain variant, and additional monoclonals 11F5, 12F5, and 19C7 (identical to 6B3), that specifically bind the PDGF-CC active/core region. Variable heavy and light chain sequences and complementary determining regions are specified, and epitope mapping localizes binding within the PDGF-C active domain comprising residues 231–345. The antibodies bind PDGF-CC with low-nanomolar apparent KD and exhibit specificity versus PDGF-D while retaining high affinity after humanization.
These antibodies neutralize PDGF-CC signaling, including inhibition of PDGFR-α phosphorylation and endothelial cell proliferation that drive tumor growth and angiogenesis. PDGF-CC protein is elevated in many tumors versus matched normal tissue, and the invention addresses reduction of tumor growth and anti-angiogenic readouts. The disclosure provides chimeric, humanized, and affinity-matured variants and describes [procedural detail omitted for safety], assay formats, diagnostic kits, drug-screening applications, and therapeutic uses.
PDGF-CC induces blood–brain barrier opening and contributes to increased infarct volume in a humanized PDGF-CC mouse MCAO ischemic stroke model. The invention addresses closure of PDGF-CC–induced blood–brain barrier opening and reduction of infarct volume, and describes modulation or prevention of blood–brain barrier opening for cerebral edema and central nervous system pathologies including stroke.
Claims Coverage
Two independent claims are present. The claims recite antibodies that specifically interact and show measurable affinity to a polypeptide comprising the active portion of PDGF-C (SEQ ID NO:2) or a polypeptide having at least 90% sequence identity thereto, and that are defined by specified light-chain CDR sequences, alternative heavy-chain CDR sets, or by defined light and heavy chain sequence pairs. The coverage is captured in four main inventive features.
Specific interaction with the active portion of PDGF-C
An isolated antibody or antigen-binding fragment that specifically interacts and shows measurable affinity to a polypeptide comprising the active portion of PDGF-C (SEQ ID NO:2) or a polypeptide having at least 90% sequence identity thereto.
Light chain CDR set defined by SEQ ID NOs 16, 17, 18
A light chain complementary determining region set comprising CDR1L = SEQ ID NO:16, CDR2L = SEQ ID NO:17, and CDR3L = SEQ ID NO:18 as the light chain definition of the claimed antibody.
Alternative heavy chain CDR sets
A heavy chain complementary determining region set defined as one of: (i) CDR1H = SEQ ID NO:34, CDR2H = SEQ ID NO:35, CDR3H = SEQ ID NO:36; (ii) CDR1H = SEQ ID NO:46, CDR2H = SEQ ID NO:47, CDR3H = SEQ ID NO:48; or (iii) CDR1H = SEQ ID NO:49, CDR2H = SEQ ID NO:50, CDR3H = SEQ ID NO:51.
Defined light and heavy chain sequence pairs
An antibody or antigen-binding fragment comprising a light chain and a heavy chain having the respective full sequences of (i) SEQ ID NOs:4 and 10, (ii) SEQ ID NOs:8 and 14, or (iii) SEQ ID NOs:9 and 15, combined with specific interaction and measurable affinity to the polypeptide comprising the active portion of PDGF-C (SEQ ID NO:2) or a ≥90% identical polypeptide.
The independent claims cover antibodies that bind the active portion of PDGF-C with measurable affinity, defined by a specified light chain CDR set together with one of several alternative heavy chain CDR sets, or by explicit light/heavy chain sequence pairs.
Stated Advantages
High specificity for PDGF-CC versus PDGF-D and low-nanomolar apparent KD, with retained neutralizing activity after humanization.
Therapeutic utility in cancer by reducing tumor growth and decreasing tumor vessel number and area (anti-angiogenic effect).
Modulation or prevention of blood–brain barrier opening, including closure of PDGF-CC–induced blood–brain barrier opening.
Treatment of central nervous system pathologies, including stroke, with significant reduction of infarct volume.
A chimeric 6B3 (ch6B3) retaining binding affinity is produced [procedural detail omitted for safety].
Diagnostic detection of PDGF-C using diagnostic kits.
Documented Applications
Cancer therapy and anti-angiogenic use as demonstrated by reduced tumor growth and vessel number/area in colon and breast xenografts [procedural detail omitted for safety].
Modulation or prevention of blood–brain barrier opening and treatment of cerebral edema and central nervous system pathologies, including stroke, demonstrated by closure of PDGF-CC–induced blood–brain barrier opening and reduced infarct volume and hemorrhage scoring in a humanized PDGF-CC mouse MCAO ischemic stroke model [procedural detail omitted for safety].
Diagnostic kits for PDGF-C detection and diagnostic assays.
Drug-screening applications.
Use in assay formats including ELISA, Western blot, Biacore/SPR, and sandwich immunoassays.
Generation of partly humanized PDGF-C transgenic animals.
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