Long-acting interleukin-15 receptor agonists and related immunotherapeutic compositions and methods
Inventors
Kirk, Peter Benedict • Zhang, Ping • Brewer, Peiwen Kuo
Assignees
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Publication Number
US-12036283-B2
Publication Date
2024-07-16
Expiration Date
Abstract
The instant disclosure provides a long acting IL-15 receptor agonist, related compositions and methods of preparation and use, for example, in the treatment of conditions responsive to therapy effective to provide, for example, sustained immune activation and/or anti-tumor activity.
Core Innovation
The invention relates to a long-acting interleukin-15 (IL-15) receptor agonist composition comprising a mixture of poly(ethylene glycol)-interleukin-15 moiety conjugates according to Formula (I) and Formula (II). IL-15 is an interleukin-15 moiety, n has a value corresponding to a weight average molecular weight of the poly(ethylene glycol) of about 40,000 daltons, and m is 3. The average number of poly(ethylene glycol) moieties covalently attached to IL-15 amino groups is in a range from 1.0 to about 1.3, with n' being 1.
The composition includes specific PEG-architecture formula families, including Formula (Ia) to (Id) and Formula (IIa) to (IId), with limits on higher PEG species and the amount of Formula (II) components. The document discusses positional isomer heterogeneity in the PEG attachment while maintaining the monoPEGylated architecture. Purification can yield compositions with trace or substantially no Formula (II) content.
The conjugates provide retained activity and retained IL-15 receptor alpha binding relative to unmodified IL-15, together with reduced IL-15 deamidation. Documented performance attributes include a limited EC50 reduction versus IL-15 in CTLL-2 pSTAT5 assays and bounded reductions in receptor alpha binding.
Claims Coverage
The claim coverage centers on one independent claim defining a long-acting IL-15 receptor agonist composition with a monoPEGylated attachment average and specific conjugate parameters, together with dependent claims that further constrain potency, binding, deamidation, recombinant identity, and formulation aspects.
Long-acting PEG-interleukin-15 receptor agonist composition with monoPEGylated attachment average
A long-acting interleukin-15 (IL-15) receptor agonist composition comprising a mixture of poly(ethylene glycol)-interleukin-15 moiety conjugates according to Formula (I), wherein n' is 1, with respect to each of Formula (I) and Formula (II) m is 3, IL-15 is an interleukin-15 moiety, n has a value corresponding to a weight average molecular weight of the poly(ethylene glycol) of about 40,000 daltons, and the average number of poly(ethylene glycol) moieties covalently attached to IL-15 amino groups for the conjugates of Formula (I) and Formula (II) is in a range from 1.0 to about 1.3.
Conjugate potency and receptor alpha binding retention within defined limits
Relative to unmodified IL-15, the EC50 is reduced by no more than about 2-fold and the IL-15 receptor alpha KD is reduced by no more than about 50%.
Reduced IL-15 deamidation level in conjugates
The conjugates have less than about 35% deamidation.
Recombinant human IL-15 moiety
The IL-15 moiety defined by Formula (I) and Formula (II) is recombinant human IL-15.
Potassium phosphate buffer in the IL-15 receptor agonist formulation
The long-acting IL-15 receptor agonist is characterized in that potassium phosphate is the buffer.
The core inventive structure is a long-acting monoPEGylated PEG-interleukin-15 conjugate mixture with an average PEG covalent attachment level of about 1.0 to about 1.3, using conjugates defined by Formula (I) and Formula (II) with m=3 and PEG weight-average about 40,000 daltons, while maintaining functional retention and reduced deamidation, with formulation specifics including potassium phosphate buffer.
Stated Advantages
Retained activity relative to unmodified IL-15, with EC50 reduced by no more than about 2-fold.
Retained IL-15 receptor alpha binding relative to unmodified IL-15, with IL-15 receptor alpha KD reduced by no more than about 50%.
Reduced IL-15 deamidation, with conjugates having less than about 35% deamidation.
Maintains a monoPEGylated overall PEG substitution average and an average number of PEG moieties covalently attached to IL-15 amino groups from about 1.0 to about 1.3.
Documented Applications
Immunotherapeutic effects including NK activation and proliferation.
Immunotherapeutic effects including CD8 survival and memory formation.
Cancer treatment.
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