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Publication Number
US-12642840-B2
Publication Date
2026-06-02
Expiration Date
Abstract
The present invention provides, among other things, methods of using IL-2 fusion proteins, comprising an IL-2 variant and an Pc region, to treat and/or prevent heart transplant rejections. Methods of treating heart disease or a symptom thereof, conditioning a subject for heart transplant, modulating immunosuppression, and selectively increasing regulatory T cells are also disclosed.
Core Innovation
The invention relates to IL-2-based agents for preventing or treating transplant rejection, including heart transplant rejection. The approach conditions a subject prior to a heart transplant by administering an effective amount of an IL-2 variant or IL-2 mutein that selectively increases regulatory T cells (Tregs).
The IL-2 variant has reduced receptor binding affinity associated with CD25 and/or reduced binding affinity to CD122/CD132, with low-affinity binding to the CD122/CD132 heterodimer and reduced CD25 binding. The selective functional profile is associated with activity toward Foxp3+ T cells and Tregs while reducing off-target activation of T effector cells and NK cells.
In certain embodiments, the IL-2 variant is an IL-2 fusion protein with an Fc region, including an IgG1 allotype m3 with N297G substitution and a C-terminal fusion configuration. The disclosure further describes linkers such as a (G4S)4 linker (SEQ ID NO: 48), an option of dimerization, and IL-2 variants and fusion proteins defined by specific SEQ ID numbers including SEQ ID NO: 5, SEQ ID NO: 1008, and SEQ ID NO: 1003.
Claims Coverage
The claim coverage centers on conditioning a subject prior to a heart transplant using an IL-2 variant having the amino acid sequence of SEQ ID NO: 5. The inventive features include the specific IL-2 variant sequence, Fc fusion protein embodiments with defined Fc and linker sequences, and optional combination with rapamycin.
Conditioning with an IL-2 variant of SEQ ID NO: 5
A method of conditioning a subject prior to a heart transplant by administering to a subject in need thereof an effective amount of an IL-2 variant comprising the amino acid sequence of SEQ ID NO: 5, thereby conditioning the subject prior to the heart transplant.
IL-2 Fc fusion protein with defined Fc and linker
Fusing the IL-2 variant to an Fc region to form an IL-2 Fc fusion protein, including the amino acid sequence of SEQ ID NO: 1008, with the Fc region including the amino acid sequence of SEQ ID NO: 1003 and the linker comprising (G4S)4 (SEQ ID NO: 48).
IL-2 conditioning with rapamycin
Conditioning the subject using the IL-2 variant regimen in combination with an immunosuppressive agent including rapamycin.
Overall, the claim coverage is centered on conditioning prior to a heart transplant by administering an IL-2 variant defined by SEQ ID NO: 5, with dependent refinements covering IL-2 Fc fusion constructs using specified Fc and linker elements and optional combination with rapamycin.
Stated Advantages
Selective activity toward Foxp3+ T cells and Tregs while reducing off-target activation of T effector cells and NK cells.
Low-affinity binding to the CD122/CD132 heterodimer with reduced CD25 binding.
Enhanced stability and half-life associated with stabilizing mutations.
Reduced incorrect disulfide pairing.
FcRn-mediated half-life extension and effects attributable to Fc glycosylation.
Increases regulatory T cell (Treg) levels.
Improved potency and selectivity for Tregs.
Modulates immunosuppression, including in combination contexts involving rapamycin.
Documented Applications
Conditioning a subject prior to a heart transplant using an IL-2 variant comprising the amino acid sequence of SEQ ID NO: 5.
Treatments including transplant rejection.
Preventing or treating transplant rejection, including heart transplant rejection.
Selectively expanding regulatory T cells (Tregs), including FoxP3+ T cells.
Conditioning for allograft survival.
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