IL-15/IL-15RA heterodimeric Fc fusion proteins and uses thereof
Inventors
Bernett, Matthew • Desjarlais, John • Rashid, Rumana • Varma, Rajat • Bonzon, Christine
Assignees
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Publication Number
US-12239688-B2
Publication Date
2025-03-04
Expiration Date
Abstract
The present invention is directed to novel IL-15/IL-15Rα heterodimeric Fc fusion proteins and uses thereof. The IL-15/IL-15Rα heterodimeric Fc fusion proteins can be administered to a patient to treat cancer. In some cases, the IL-15/IL-15Rα heterodimeric Fc fusion protein is administered in combination with a checkpoint blockage antibody such as a PD-1 antibody.
Core Innovation
The invention provides engineered IL-15/IL-15Rα heterodimeric Fc fusion protein formats defined by specific IL-15 receptor alpha sushi-domain content and an IL-15 variant domain paired with variant human IgG1 Fc domains. A first monomer includes an IL-15Rα sushi domain, a first domain linker, and a first variant Fc domain comprising CH2-CH3, while a second monomer includes a variant IL-15 domain, a second domain linker, and a second variant Fc domain comprising CH2-CH3.
The IL-15 variant domain is described using the amino acid sequence of SEQ ID NO:2 together with specific amino acid substitutions selected from N4D/N65D, D30N/N65D, and D30N/E64Q/N65D. The Fc portions are described as human IgG1 Fc domain variants with defined EU-numbered substitution sets, including S267K/L368D/K370S:S267K/S364K/E357Q, S364K/E357Q:L368D/K370S, L368D/K370S:S364K, L368E/K370S:S364K, T411E/K360E/Q362E:D401K, L368D/K370S:S364K/E357L, and K370S:S364K/E357Q.
The document places these engineered IL-15/IL-15Rα Fc fusions in combination with checkpoint blockade antibodies, specifically anti-PD-L1 antibodies, and describes the therapeutic context. The method is directed to inducing T cell expansion in a patient by administering a therapeutically effective amount of the IL-15/IL-15Rα heterodimeric Fc fusion protein together with a therapeutically effective amount of an anti-PD-L1 antibody.
Claims Coverage
The independent claim coverage centers on one method claim. The inventive features comprise a defined IL-15/IL-15Rα heterodimeric Fc fusion protein architecture and combination with a therapeutically effective anti-PD-L1 antibody to induce T cell expansion.
Inducing T cell expansion with IL-15/IL-15Rα Fc fusion plus anti-PD-L1
A method of inducing T cell expansion in a patient by administering a therapeutically effective amount of an IL-15/IL-15Rα heterodimeric Fc fusion protein, where a first monomer includes an IL-15Rα sushi domain linked to a first variant Fc domain comprising CH2-CH3, and a second monomer includes a variant IL-15 domain comprising the amino acid sequence of SEQ ID NO:2 with substitutions selected from N4D/N65D, D30N/N65D, and D30N/E64Q/N65D linked to a second variant Fc domain comprising CH2-CH3, with the first and second variant Fc domains being human IgG1 Fc variants having EU-numbered substitution sets selected from specified Fc skew variant pairings, and further administering a therapeutically effective amount of an anti-PD-L1 antibody.
The claimed inventive concept is a defined IL-15/IL-15Rα heterodimeric Fc fusion protein architecture administered together with a therapeutically effective anti-PD-L1 antibody to induce T cell expansion.
Stated Advantages
Enhanced T/NK cell proliferation/expansion.
Reduces vascular leakage and associated hypoalbuminemia risk.
Associated with pharmacodynamic outcomes including IFNγ and tumor size reduction.
Documented Applications
Inducing T cell expansion in a patient by administering an IL-15/IL-15Rα Fc fusion protein together with an anti-PD-L1 antibody.
Checkpoint-blockade antibody co-therapy compositions are described, including anti-PD-1 antibodies (nivolumab, pembrolizumab, pidilizumab), in connection with the IL-15/IL-15Rα Fc fusion approach.
Cancer therapy by inducing T cell expansion in a patient using an IL-15/IL-15Rα Fc fusion protein in combination with checkpoint blockade antibodies, including anti-PD-L1 antibodies.
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