Pharmaceutical composition for treatment of cancer, comprising an immune checkpoint inhibitor antibody and a fusion protein comprising an IL-2 mutant and a CD80 extracellular domain
Inventors
Jang, Myoung Ho • Nam, Su Youn • Koh, Young Jun • Cho, Young-Gyu
Assignees
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Publication Number
US-11639383-B2
Publication Date
2023-05-02
Expiration Date
Abstract
There is provided a pharmaceutical composition for preventing or treating cancer comprising, as active ingredients, a fusion protein dimer comprising an IL-2 protein or a variant thereof and a CD80 protein or a fragment thereof, and an immune checkpoint inhibitor. The fusion protein containing an CD80 fragment, an Fc domain of an immunoglobulin, and an IL-2 variant in an embodiment can activate immune cells such as natural killer cells as well as control the immune cell regulatory activity of regulatory T cells. In addition, the combined administration of the fusion protein and an immune checkpoint inhibitor such as Keytruda known as a PD-1 inhibitor can effectively inhibit cancer. Therefore, a pharmaceutical composition containing, as active ingredients, a fusion protein dimer comprising an IL-2 protein or a variant thereof and a CD80 protein or a fragment thereof, and an immune checkpoint inhibitor can be effectively applied to the treatment of cancer and has high industrial applicability.
Core Innovation
The invention relates to a cancer treatment pharmaceutical composition that combines an IL-2 protein variant with an extracellular domain of CD80 as a fusion protein dimer, together with an immune checkpoint inhibitor. The fusion protein dimer comprises an IL-2 protein variant containing substitutions of the 38th and 42nd in the amino acid of SEQ ID NO: 10 and an extracellular domain of CD80 protein.
The composition further includes an immune checkpoint inhibitor selected from anti-PD-1, anti-PD-L1, or anti-TIGIT antibodies. The described fusion protein dimer is configured to activate immune cells, including natural killer (NK) cells, and to provide synergy in combination with immune checkpoint inhibition.
The patent states that the approach can reduce IL-2Rα binding and lower in vivo toxicity, including vascular (capillary) leakage syndrome (VLS). The provided concepts include use of IL-2 variants with substitutions and CD80 extracellular domain configurations, and support is described by binding affinity measurements and immune functional assays, as well as in vivo tumor efficacy showing improved tumor growth inhibition with checkpoint antibodies.
Claims Coverage
The independent claims cover a pharmaceutical composition including a CD80/IL-2 fusion protein dimer with specific IL-2 substitutions and an immune checkpoint inhibitor selected among anti-PD-1, anti-PD-L1, and anti-TIGIT antibodies. Only one independent claim is explicitly provided in the partial content, with dependent claims refining linkage, CD80 extracellular domain boundaries, and selection of specific anti-PD-1 and anti-PD-L1 antibodies.
IL-2 variant fused to CD80 extracellular domain as a dimer
A pharmaceutical composition comprising a fusion protein dimer comprising an IL-2 protein variant comprising substitutions of the 38th and 42nd in the amino acid of SEQ ID NO: 10 and an extracellular domain of CD80 protein.
Immune checkpoint inhibitor selected from anti-PD-1, anti-PD-L1, or anti-TIGIT
The pharmaceutical composition further includes an immune checkpoint inhibitor selected from the group consisting of an anti-PD-1 antibody, an anti-PD-L1 antibody and an anti-TIGIT antibody.
Linking IL-2 variant to CD80 via a linker
A pharmaceutical composition in which an IL-2 protein variant is linked to the extracellular domain of a CD80 protein through a linker.
CD80 extracellular domain defined by an amino-acid range
The extracellular domain of CD80 comprises amino acids 35 to 242 of SEQ ID NO: 11.
Fusion protein having the amino acid sequence SEQ ID NO: 9
A pharmaceutical composition includes a fusion protein having the amino acid sequence specified as SEQ ID NO: 9.
Selected anti-PD-1 and selected anti-PD-L1 antibody options
The pharmaceutical composition includes a selected anti-PD-1 antibody from a specified list and a selected anti-PD-L1 antibody from a specified list.
Overall, the claim coverage is directed to a pharmaceutical composition that pairs an IL-2 variant (substitutions at the 38th and 42nd positions of SEQ ID NO: 10) fused to a CD80 extracellular domain as a fusion protein dimer with an immune checkpoint inhibitor selected among anti-PD-1, anti-PD-L1, and anti-TIGIT, with dependent refinements specifying linker use, CD80 extracellular domain boundaries, a defined fusion protein sequence, and enumerated selections of anti-PD-1 and anti-PD-L1 antibodies.
Stated Advantages
The composition can reduce IL-2Rα binding.
The composition can lower in vivo toxicity, including vascular (capillary) leakage syndrome (VLS).
The composition provides improved tumor growth inhibition in combination with checkpoint antibodies, including synergy with immune checkpoint inhibition.
Documented Applications
Cancer treatment pharmaceutical compositions comprising the CD80/IL-2 fusion protein dimer together with immune checkpoint inhibitor antibodies.
Combination use with checkpoint antibodies including anti-PD-1 (e.g., Keytruda/pembrolizumab), anti-PD-L1, and anti-TIGIT in tumor efficacy contexts described in the partial content.
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