Heterodimeric Fc-fused proteins
Inventors
Cheung, Ann F. • Cuillerot, Jean-Marie • Grinberg, Asya • GUTIERREZ, EVA • Haney, William • Wagtmann, Nicolai
Assignees
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Publication Number
US-11787864-B2
Publication Date
2023-10-17
Expiration Date
Abstract
The present invention provides Fc-fused protein constructs, which as monovalent dimers have a higher serum half-life compared to a native/natural molecule, and are, therefore, advantageous for achieving higher titers of the proteins during production, higher stability during storage, and improved efficacy when used as a therapeutic. Also provided are Fc-fused protein constructs having mutations in the Fc region that reduce effector functions, which have increased activity to inhibit tumor growth and are, therefore, advantageous when used as a cancer therapy.
Core Innovation
The invention concerns heterodimeric Fc-fused protein constructs in which a first polypeptide comprises a first human IgG1 Fc domain fused to a p40 subunit of human IL-12, and a second, different polypeptide comprises a second human IgG1 Fc domain fused to a p35 subunit of human IL-12, with the p40 and p35 subunits bound to each other. Heterodimerization is controlled by specified CH3 domain substitutions in the human IgG1 Fc domains, including Y349C, K360E, and K409W in the first Fc domain and Q347R, D399V, F405T, and S354C in the second Fc domain.
Each polypeptide further includes CH2 domain substitutions L234A, L235A, and P329A, and defined linker sequences connect the Fc domains to the IL-12 subunits. The constructs specify linker amino acid sequences including PKSSDKTHTCPPCPAPEAAG or PKSSDKTHTCPPCPAPEAAGG for the first polypeptide and a G-rich flexible sequence linked to the same motif or GGGGSGGGGSGGGGSEPKSSDKTHTCPPCPAPEAAGG for the second polypeptide. The first and second polypeptides are further defined by amino acid sequences SEQ ID NO:290 and SEQ ID NO:291.
The document further characterizes the heterodimeric IL-12-Fc constructs in terms of serum half-life and tumor retention, and it discusses formulation and therapeutic applications consistent with the pharmaceutical composition and administration contexts. Overall, the core substantive value is the molecular design of heterodimeric IL-12-Fc constructs based on specified Fc domain mutations, defined linker architecture, and complete polypeptide identities.
Claims Coverage
The independent claims define a heterodimeric Fc-fused IL-12 construct with complementary Fc CH3 and CH2 substitutions and defined linker amino-acid sequences, and one independent claim further defines a pharmaceutical composition comprising the construct and a pharmaceutically acceptable carrier. The claims cover two principal inventive features.
Heterodimeric Fc-fused IL-12 with complementary Fc CH3 and CH2 substitutions and defined linkers
A heterodimeric Fc-fused protein comprising a first polypeptide with a first human IgG1 Fc domain containing CH3 domain substitutions Y349C, K360E, and K409W and fused to a p40 subunit, and a second polypeptide with a second human IgG1 Fc domain containing CH3 domain substitutions Q347R, D399V, F405T, and S354C and fused to a p35 subunit, with each polypeptide containing specified linker sequences connecting its Fc domain to its IL-12 subunit, and with CH2 domain substitutions L234A, L235A, and P329A in both Fc domains, wherein the first and second IL-12 subunits are bound to each other.
Pharmaceutical composition with heterodimeric Fc-fused IL-12 and pharmaceutically acceptable carrier
A pharmaceutical composition comprising a heterodimeric Fc-fused protein and a pharmaceutically acceptable carrier, where the heterodimeric Fc-fused protein includes a first polypeptide with a p40 subunit fused to a human IgG1 Fc domain containing CH3 substitutions Y349C, K360E, and K409W and CH2 substitutions L234A, L235A, and P329A, and a second polypeptide with a p35 subunit fused to a human IgG1 Fc domain containing CH3 substitutions Q347R, D399V, F405T, and S354C and CH2 substitutions L234A, L235A, and P329A, with specified linker sequences and the first and second IL-12 subunits bound to each other.
Overall, the claim coverage centers on a heterodimeric IL-12 Fc-fused protein in which complementary CH3 substitutions enable heterodimerization and disulfide pairing between a p40-Fc and a p35-Fc polypeptide, while shared CH2 substitutions are included in both Fc domains, and defined linker sequences connect each IL-12 subunit to its Fc domain. The second independent claim extends this construct into a pharmaceutical composition with a pharmaceutically acceptable carrier.
Stated Advantages
Superior tumor regression and survival versus wildtype IL-12-Fc and native IL-12 in CT26 and B16F10 models.
Prolonged half-life/exposure and maintained IFNγ activity.
Induction of cytokines including IFNγ and CXCL9/10.
Reduced engagement of FcγR for LALAPA/LALAPG variants while retaining functional activity.
Enhanced combination therapy performance, including with PD-1 blockade, TriNKETs, chemotherapy, and radiation, with abscopal effects and immunological memory upon rechallenge.
Serum half-life and tumor retention are discussed.
Documented Applications
Treating tumors in CT26 and B16F10 models using IL-12 Fc-fused heterodimeric proteins, with efficacy evaluated by tumor regression and survival.
Combination therapy use with PD-1 blockade and with TriNKETs.
Combination therapy use with chemotherapy and radiation.
Oncolytic virus therapy combination contemplated with T-VEC (IMLYGIC) for treating melanoma/skin cancer.
Use in contexts involving rechallenge to demonstrate immunological memory.
Pharmaceutical compositions suitable for intravenous administration.
Pharmaceutical compositions suitable for subcutaneous administration.
Pharmaceutical compositions suitable for intraperitoneal administration.
Pharmaceutical compositions suitable for intratumoral administration.
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