IL-12 heterodimeric Fc-fusion proteins
Inventors
Bernett, Matthew • Desjarlais, John R. • Varma, Rajat • Liu, Ke • Hassanzadeh-Kiabi, Nargess • Rashid, Rumana
Assignees
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Publication Number
US-12234270-B2
Publication Date
2025-02-25
Expiration Date
Abstract
The present invention provides novel IL-12 Fc fusion proteins, methods of making and using the same. The IL-12 Fc fusion proteins are useful for treatment of cancer and can be used in combination with checkpoint blockade.
Core Innovation
The invention relates to IL-12 Fc fusion protein compositions including heterodimeric and homodimeric Fc fusion architectures for cancer treatment. The heterodimeric Fc fusion combines an IL-12p40-variant domain fused to one Fc domain with an IL-12p35 domain fused to another Fc domain, and the Fc portions include Fc mutations that promote heterodimerization. The variant IL-12p40 subunit domains include amino-acid substitution patterns such as E59K, E59K/K99Y, and E59K/K99Y/C252S, with sequence identity requirements relative to SEQ ID NO: 4 in some embodiments.
The document further describes Fc-domain interface substitutions designed to promote heterodimerization versus homodimerization, including heterodimerization-promoting substitutions using EU numbering and additional Fc substitutions. It identifies functional pairing examples such as S364K/E357Q and L368D/K370S, and includes additional Fc substitutions for half-life extension, including M428L/N434S. The fusion protein architecture is described as a Fc domain-linkers-IL-12 subunits arrangement, with optional symmetry of first and second domain linkers and additional Fc substitution sets as part of the polypeptide composition.
The disclosed compositions further encompass nucleic acids encoding the IL-12 Fc fusion proteins, host cells, and production and purification statements at a high level. The overall compositions include engineered variants and sequence-identity constraints, and are described for therapeutic use in cancer treatment, including embodiments optionally combined with checkpoint blockade.
Claims Coverage
The independent claims are directed to compositions comprising variant IL-12p40 subunit domains with defined substitution patterns and a sequence-identity requirement relative to SEQ ID NO: 4. Across the claims, the inventive features focus on restricting the allowed IL-12p40 substitutions and requiring at least 90% sequence identity to a reference sequence. Two closely related inventive feature sets are present.
Variant IL-12p40 subunit domain with defined substitution set and sequence identity threshold
A composition comprising a variant IL-12p40 subunit domain with amino acid substitutions selected from E59K, E59K/K99Y, and E59K/K99Y/C252S, wherein the variant IL-12p40 subunit domain has at least 90% sequence identity to SEQ ID NO: 4.
Specific E59K/K99Y/C252S IL-12p40 variant and sequence identity threshold
A composition comprising a variant IL-12p40 subunit domain comprising E59K/K99Y/C252S amino acid substitutions, wherein the variant IL-12p40 subunit domain has at least 90% sequence identity to SEQ ID NO: 4.
The independent claim coverage is limited to compositions containing an IL-12p40 variant subunit domain with either the specified E59K-based substitution combinations or the specific E59K/K99Y/C252S combination, with the variant domain required to have at least 90% sequence identity to SEQ ID NO: 4.
Stated Advantages
Increases in lymphocytes after IL-12 Fc administration.
Increases in peripheral CD8+ T cells after IL-12 Fc administration.
At least a 2-fold T cell expansion.
Administration of IL-12 Fc before the checkpoint inhibitor is specified to increase checkpoint expression prior to treatment.
Documented Applications
Treating cancer in a subject or patient using heterodimeric or homodimeric IL-12 Fc fusion proteins.
Inducing T cell expansion using heterodimeric or homodimeric IL-12 Fc fusion proteins.
Combination cancer immunotherapy with checkpoint blockade antibodies including anti-PD-1, anti-PD-L1, anti-TIM3, anti-TIGIT, anti-LAG3, and anti-CTLA-4, with IL-12 Fc administered before the checkpoint inhibitor.
Treating cancer, optionally with checkpoint blockade.
In vivo anti-tumor and GVHD studies in the context of the therapeutic compositions.
Use of anti-LAG-3 antibody molecules, including clinical anti-LAG-3 antibodies BMS-986016 and LAG525.
Cancer treatment.
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