UPAR antibodies and fusion proteins with the same
Inventors
Dong, Jijun • Gurel, Pinar • Heiber, Joshua • Hu, Yuan
Assignees
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Publication Number
US-12338293-B2
Publication Date
2025-06-24
Expiration Date
Abstract
The disclosure provides urokinase plasminogen activator receptor (uPAR) binding polypeptides (e.g., uPAR antigen binding proteins), and fusion proteins comprising said uPAR binding polypeptides and a cytokine or variant thereof. The disclosure further provides pharmaceutical compositions comprising the uPAR binding polypeptides and fusion proteins of the disclosure and methods of treating cancer with the same. The disclosure further provides engineered IL-12 p35 and p40 polypeptides.
Core Innovation
The invention provides a kit comprising two pharmaceutical compositions, each containing a different fusion protein for targeting urokinase plasminogen activator receptor (uPAR). The first pharmaceutical composition includes a first fusion protein that binds specifically to a first uPAR epitope with an antigen binding domain having defined heavy chain variable domain CDRs and defined light chain variable domain CDRs, and comprises an IL-12 p35 subunit comprising SEQ ID NO: 81, optionally with selected amino acid substitutions in SEQ ID NO: 81.
The second pharmaceutical composition includes a second fusion protein that binds specifically to a second uPAR epitope with an antigen binding domain having defined heavy chain variable domain CDRs and defined light chain variable domain CDRs, and comprises an IL-12 p40 subunit comprising SEQ ID NO: 84, optionally with one or two specified amino acid substitutions in SEQ ID NO: 84. Together, the kit architecture links uPAR epitope-specific antigen binding domains to IL-12 p35 or IL-12 p40 subunits in two separate fusion protein compositions.
The document describes embodiments in which two different fusion proteins, each carrying a distinct uPAR epitope-binding antigen binding domain and a distinct IL-12 subunit, are used in combination for administration. The described approach addresses therapeutic and prophylactic in vivo efficacy for cancers described as uPAR-expressing tumor.
Claims Coverage
The document provides one independent claim directed to a kit, comprising two pharmaceutical compositions with two defined uPAR-targeting IL-12 fusion proteins. The inventive features cover dual uPAR epitope-specific antigen binding domains and IL-12 p35 versus IL-12 p40 subunits with defined sequence identifiers and optional substitution sets.
Dual fusion-protein kit with uPAR epitope-specific antigen binding and IL-12 p35/p40 subunits
A kit comprising a first pharmaceutical composition comprising a first fusion protein and a second pharmaceutical composition comprising a second fusion protein, where the first fusion protein binds specifically to a first uPAR epitope with an antigen binding domain having heavy chain variable domain CDR1, CDR2, CDR3 of SEQ ID NOs: 41, 20, 21 respectively, and light chain variable domain CDR1, CDR2, CDR3 of SEQ ID NOs: 22-24 respectively, and comprises an IL-12 p35 subunit comprising SEQ ID NO: 81 optionally with selected amino acid substitutions in SEQ ID NO: 81; and where the second fusion protein binds specifically to a second uPAR epitope with an antigen binding domain having heavy chain variable domain CDR1, CDR2, CDR3 of SEQ ID NOs: 3-5 respectively, and light chain variable domain CDR1, CDR2, CDR3 of SEQ ID NOs: 6-8 respectively, and comprises an IL-12 p40 subunit comprising SEQ ID NO: 84 optionally with one or two of specified amino acid substitutions in SEQ ID NO: 84.
Across the independent kit claim, the core coverage is the combination of two separate uPAR-targeting fusion protein compositions: one fusion protein that carries a defined IL-12 p35 subunit and binds a first uPAR epitope, and a second fusion protein that carries a defined IL-12 p40 subunit and binds a second uPAR epitope, with optional substitution sets defined for the IL-12 subunits and defined sequence identifiers defining the antigen-binding CDRs.
Stated Advantages
Improved tumor penetration for uPAR-targeted SEQ ID NO:110 versus control SEQ ID NO:94, based on tumor/serum pharmacokinetics (T/S ratios).
Tumor detection across timepoints and serum clearance behavior are reported for selected anti-uPAR–IL-12 fusion proteins in SC RKO xenografts.
Documented Applications
uPAR-targeted anti-uPAR–IL-12 fusion protein assessment including binding to human/mouse uPAR, cellular signaling readouts (e.g., STAT5 phosphorylation), and binding to uPAR+ mouse tumor lines (4T1, CT26, EMT6, MC38).
Pharmacokinetics and tumor targeting evaluation in an SC RKO xenograft model, including tumor detection across timepoints and serum clearance behavior.
Functional activity assessment using receptor/signaling readouts reported in the document, including IL-10, IL-12, and 4-1BB/GM-CSF receptor activation, and IL-12 reporter signaling (HEK-Blue IL-12 cells with NF-κB/AP-1; SEAP reporter).
Therapeutically or prophylactically administering the described kit/fusion proteins for uPAR-expressing cancers.
Monitoring and evaluating in vivo efficacy for tumor versus serum clearance and tumor accumulation characteristics associated with the fusion protein compositions.
Assessing functional IL-12 activity readouts associated with the described fusion proteins in vitro and in vivo, including signal associated with Stat4 phosphorylation and IFN-γ production [procedural detail omitted for safety].
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