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Publication Number
US-12486311-B2
Publication Date
2025-12-02
Expiration Date
Abstract
The present application relates to CTLA4-Ig immunoadhesins that target CD80 and CD86, and their use, particularly for therapeutic purposes.
Core Innovation
The disclosure describes a CTLA4-Ig immunoadhesin that targets B7-1 (CD80) and B7-2 (CD86) using a variant CTLA4 extracellular-domain fused to an Ig Fc region. The variant CTLA4 is defined relative to SEQ ID NO: 6 with EU amino acid numbering and includes amino acid substitutions A29H, T51N, L61E, and K93Q. The Ig Fc region is defined with substitutions M428L/N434S to improve FcRn-related properties.
The disclosure further specifies that the CTLA4-Ig immunoadhesin includes additional CTLA4 variant substitutions and can use IgG subclasses selected from IgG1, IgG2, or an IgG1/IgG2 hybrid. The described variant and Fc substitution combinations are presented as improving binding kinetics and T-cell inhibitory function. The document emphasizes CTLA4 extracellular-domain variants together with Fc region variants to achieve these combined functional effects.
The disclosure provides experimental support for improved functional performance, including improved B7 binding kinetics measured by Biacore/SPR parameters such as koff and KD, and stronger in vitro T-cell inhibitory activity. In vitro assays are described in the context of CD86/CD3 co-ligation and a mixed lymphocyte reaction with IL-2 readout. The disclosure also describes enhanced in vivo suppression of human anti-tetanus IgG in SCID-humanized mice.
Claims Coverage
The partial claims provided include one independent claim directed to the CTLA-4 fusion protein structure. The inventive features specifically cover a defined variant CTLA-4 together with a defined IgG Fc region containing Fc substitutions, and further define additional variant options and subclass/production/method aspects through dependent claims.
Variant CTLA-4 with EU-index substitutions fused to IgG Fc region
A CTLA-4-fusion protein comprising a variant CTLA-4 as compared to SEQ ID NO: 6 and an IgG Fc region, wherein the variant CTLA-4 comprises amino acid substitutions A29H, T51N, L61E, and K93Q (EU index), and wherein the IgG Fc region comprises M428L/N434S substitutions (EU index numbering).
Additional CTLA-4 variant substitution options
The CTLA-4-fusion protein further comprises a variant CTLA-4 including an E31I, E31T, or E31M mutation.
Additional CTLA-4 I106 mutation selection
The CTLA-4-fusion protein further includes an additional CTLA-4 variant containing an I106 mutation selected from I106E or I106Y.
IgG1 immunoglobulin subclass selection
The CTLA-4-fusion protein is specified to use an IgG1 immunoglobulin.
Cultured host cell production and purification of the CTLA-4 fusion protein
A method for producing a variant CTLA-4-fusion protein by culturing a cultured host cell under production conditions and purifying the resulting fusion protein.
Across the independent claim and its dependent refinements, the coverage centers on a CTLA-4-fusion protein that combines a defined CTLA-4 variant (A29H/T51N/L61E/K93Q relative to SEQ ID NO: 6 using EU numbering) with an IgG Fc region containing M428L/N434S substitutions, with further specification of additional CTLA-4 substitutions, IgG subclass selection (including IgG1), and production by culturing and purification.
Stated Advantages
Improved B7 binding kinetics, including improved Biacore/SPR parameters (koff and KD).
Stronger in vitro T-cell inhibitory activity.
Enhanced in vivo suppression of human anti-tetanus IgG in SCID-humanized mice.
Documented Applications
Inhibiting T cell activation in the presence of B7-expressing antigen-presenting cells (APCs).
Suppression of human anti-tetanus IgG in SCID-humanized mice.
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