Interleukin-2 polypeptide conjugates and their uses

Inventors

CHEN, Sigeng • Lu, Yingchun • RASHID, MD HARUNUR • KNUDSEN, Nickolas • Tian, Feng

Assignees

Ambrx Inc

Abstract

The present invention provides methods for targeting interleukin-2 receptor-expressing cells, and, in particular, inhibiting the growth of such cells by using an interleukin-2 (IL-2) variant conjugated to a biologically active molecule that will affect cells expressing the interleukin-2 receptor.

Core Innovation

The invention relates to an IL-2 polypeptide conjugate in which an IL-2 polypeptide having the amino acid sequence of SEQ ID NO: 2 comprises one non-natural amino acid incorporated into position 45. In the illustrated embodiment, the non-natural amino acid is para-acetyl-phenylalanine, and the IL-2 polypeptide is conjugated to one water-soluble polymer through the non-natural amino acid via a non-cleavable linker.

The resulting IL-2 polypeptide conjugate has reduced interaction with IL-2 receptor alpha compared to wild-type IL-2. The disclosure further describes PEGylated IL-2 conjugates and water-soluble polymer conjugates, including non-cleavable oxime linkage embodiments and PEG moieties with molecular weight constraints.

The disclosure also includes orthogonal conjugation chemistry using azide/alkyne groups via Huisgen [3+2] cycloaddition (“click chemistry”), selector codons, orthogonal tRNA/RS, and incorporation of diverse non-naturally encoded amino acids into defined positions. It further emphasizes altered properties including stability, half-life, solubility, biodistribution, and reactivity, and describes compositions intended for treatment, including prophylactic and therapeutic use.

Claims Coverage

The independent claim coverage is directed to an IL-2 polypeptide conjugate that incorporates para-acetyl-phenylalanine at position 45 and links the conjugate to a water-soluble polymer via a non-cleavable linker, with reduced interaction with IL-2 receptor alpha compared to wild-type IL-2. Dependent claims further refine the linker type, the PEG polymer constraints, the production context, and the treatment indication.

Overall claim coverage is directed to IL-2 polypeptide conjugates built from an SEQ ID NO: 2 variant containing para-acetyl-phenylalanine at position 45, conjugated through that residue to a water-soluble polymer via a non-cleavable linker, including oxime linkage. The claimed conjugates are characterized by reduced interaction with IL-2 receptor alpha compared to wild-type IL-2, with additional narrowing to PEG molecular weight constraints, mammalian-cell production context, and treatment of cancer.

Stated Advantages

Documented Applications