Anti-Gal3 antibodies and uses thereof
Inventors
Sun, Dongxu • Wang, Yan • Wu, Yinan • GORDON, Catherine A. • Williams, Samuel A. F.
Assignees
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Publication Number
US-11427638-B2
Publication Date
2022-08-30
Expiration Date
Abstract
Disclosed herein are antibodies that specifically bind to Gal3 and methods of use thereof. In some embodiments, also described herein are methods of inducing immune activation or promoting T cell or Natural Killer cell proliferation with an antibody that specifically binds to Gal3. Also disclosed herein are methods and compositions of reducing fibrosis or propensity thereof in a tissue with antibodies that specifically bind to Gal3. In some cases, the anti-Gal3 antibody also disrupts the interaction between Gal3 and TIM-3.
Core Innovation
Anti-Gal3 antibodies and anti-Gal3 conjugates are disclosed that bind Galectin-3 (Gal3) and disrupt the Gal3-TIM-3 interaction. The disclosure links Gal3-TIM-3 disruption to immune activation, including T cell and NK cell proliferation and a shift toward M1 over M2 macrophages via cytokines such as IFNγ and IL-2.
The disclosure also provides methods for reducing fibrosis by lowering fibrosis biomarker expression, including α-SMA, fibronectin, and TGF-β1, and by reducing extracellular matrix/collagen accumulation in tissues such as kidney, liver, and lung. Fibrosis-related biological markers also include TIMP-1/2, MMP-2/9, YKL-40, and HA, and anti-Gal3 targeting is described in fibrotic indications.
The invention further characterizes anti-Gal3 conjugates and constructs comprising an anti-Gal3 binding agent, including anti-Gal3 antibodies, conjugated to payload options such as cytotoxic agents, DNA-damaging agents, Akt inhibitors, polymerase and PARP inhibitors, detectable moieties, immunomodulatory agents, immunotoxins, and nucleic-acid payloads. The disclosure also includes antibody format options and linker chemistries, including PEG, polypeptide, self-immolative, and dendritic type linkers.
Claims Coverage
The independent claims define sequence-specified anti-GAL3 antibodies using exact sequence identities for antibody regions. Across the independent claims, the inventive features are characterized by CDR sequence constraints and by variable-region sequence identities, giving a total of three inventive feature sets.
Cdr-defined anti-GAL3 antibody with specified HCDR and LCDR sequences
An anti-GAL3 antibody comprising an HCDR1 comprising the sequence of SEQ ID NO: 62, an HCDR2 comprising the sequence of SEQ ID NO: 90, an HCDR3 comprising the sequence of SEQ ID NO: 118, an LCDR1 comprising the sequence of SEQ ID NO: 146, an LCDR2 comprising the sequence of SEQ ID NO: 174, and an LCDR3 comprising the sequence of SEQ ID NO: 202.
Anti-GAL3 antibody defined by heavy and light variable region sequences
An anti-GAL3 antibody comprising a heavy chain variable region comprising the sequence of SEQ ID NO: 230 and a light chain variable region comprising the sequence of SEQ ID NO: 258.
Anti-GAL3 antibody defined by heavy and light chain sequences
An anti-GAL3 antibody comprising a heavy chain comprising the sequence of SEQ ID NO: 265 and a light chain comprising the sequence of SEQ ID NO: 266.
The claim set covers anti-GAL3 antibodies defined by precise amino-acid sequence identities, either by specifying multiple CDRs, by specifying heavy and light chain variable regions, or by specifying full heavy and light chains via SEQ ID NO identifiers.
Stated Advantages
Induces immune activation, including T cell and NK cell proliferation and shifts toward M1 over M2 macrophages via cytokines such as IFN-γ and IL-2.
Reduces fibrosis by lowering fibrosis biomarker expression, including α-SMA, fibronectin, and TGF-β1, and reducing extracellular matrix/collagen accumulation in tissues such as kidney, liver, and lung.
Disrupts the Gal3-TIM-3 interaction by Gal3 binding blockade.
Reductions in tumor burden and fibrosis markers in multiple in vivo models.
Gal3-TIM-3 binding specificity and blocking by certain antibodies.
Documented Applications
Immune activation in connection with Gal3-TIM-3 disruption, including T cell and NK cell proliferation and macrophage polarization toward M1.
Reducing fibrosis in tissues such as kidney, liver, and lung, including lowering fibrosis biomarkers such as α-SMA, fibronectin, and TGF-β1 and reducing extracellular matrix/collagen accumulation.
Anti-Gal3-directed treatment in tumor models, with tumor burden reductions reported across multiple models including B16F10, 4T1, RENCA, and MC38.
Use in fibrosis model applications including kidney UUO, liver fibrosis models including N-IF, MCD NASH, and STAM CDAA-HFD, and lung bleomycin injury models.
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