IL-2 superagonists in combination with anti-PD-1 antibodies
Inventors
Merchant, Fahar • Fidai, Shafique
Assignees
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Publication Number
US-11542312-B2
Publication Date
2023-01-03
Expiration Date
Abstract
Human interleukin-2 (IL-2) muteins or variants thereof are provided. In particular, provided are IL-2 muteins that have an increased binding capacity for IL-2Rβ receptor as compared to wild-type IL-2 for use in combination therapies with anti-PD-1 antibodies for the treatment of cancer. Also provided are pharmaceutical compositions that include such anti-PD-1 antibodies and the disclosed IL-2 muteins.
Core Innovation
The invention relates to treating cancer by administering a combination treatment comprising an anti-PD-1 antibody or inhibitor or an anti-PD-L1 antibody or inhibitor or an anti-CTLA-4 antibody or inhibitor together with an IL-2 mutein. The IL-2 mutein is defined by amino acid substitutions L80F, R81D, L85V, I86V, and I92F, with numbering in accordance with the wild-type human IL-2 of SEQ ID NO:2, and the mutein comprises SEQ ID NO:9.
The combination treatment framework is described as suitable for cancer treatment and includes pharmaceutical compositions and administration frameworks. The document also describes co-formulated administration and sequential administration with IL-2 muteins, and engineered IL-2 mutein formats including fusion proteins.
Claims Coverage
The available claim content covers one independent method claim directed to treating cancer with a checkpoint-targeting agent and a specifically substituted IL-2 mutein, for a total of one inventive feature.
Checkpoint blockade with defined IL-2 mutein
A method of treating cancer comprising administering a combination treatment comprising an anti-PD-1 antibody or inhibitor or an anti-PD-L1 antibody or inhibitor or an anti-CTLA-4 antibody or inhibitor, and an IL-2 mutein comprising amino acid substitutions L80F, R81D, L85V, I86V, and I92F, wherein numbering is in accordance with the wild-type human IL-2 of SEQ ID NO:2, and wherein the IL-2 mutein comprises SEQ ID NO:9.
The claim coverage centers on the combination of checkpoint blockade and an IL-2 mutein defined by the listed substitutions relative to SEQ ID NO:2 and comprising SEQ ID NO:9 for cancer treatment.
Stated Advantages
Enhanced IL-2Rβ binding affinity/capacity.
Enhanced signaling in IL-2Rβ+ cells, including STAT5 phosphorylation, ERK1/2 signaling, and PI3-kinase signaling.
Preferential effector over Treg effects.
Reduced vascular leak syndrome.
Documented Applications
Treatment of cancer using a combination therapy including anti-PD-1/PD-L1 or anti-CTLA-4 and an IL-2 mutein with the specified substitutions.
Combination cancer therapy including anti-PD-1/PD-L1 or anti-CTLA-4 antibody or inhibitor together with an IL-2 mutein comprising SEQ ID NO:9, including treatment in contexts such as colon cancer.
Use of engineered IL-2 mutein formats including albumin/Fc fusions and antibody/targeting fusions, immune cell targeting constructs, and oncolytic virus conjugates for cancer therapy.
In a mouse MC38 colon cancer model, the document reports limited efficacy of either agent alone and increased cured mice with anti-PD-1 plus H9.
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