Cytokine-based bioactivatable drugs and methods of uses thereof

Inventors

Li, Yue-Sheng • Rui, Lingyun • Xu, Jing

Assignees

Cugene Inc

Abstract

The present disclosure provides a cytokine-based bioactivatable drug construct (“VitoKine”) platform that aims to reduce systemic mechanism-based toxicities and lead to broader therapeutic utility for proteins and cytokines such as IL-15 and IL-2 for the treatment of cancer, autoimmune diseases, inflammatory diseases, viral infection, transplantation and various other disorders. The novel VitoKine constructs of the present invention comprise: 1) a tissue or disease site targeting moiety D1 domain (“D1”), 2) a bioactivatable moiety D2 domain (“D2”), and a concealing moiety D3 domain (“D3”). Importantly, because the “active moiety” of the VitoKine construct will remain inert until activated locally by proteases that are upregulated in diseased tissues, this will limit binding of the active moiety to the receptors or to the targets in the peripheral or on the cell-surface of non-diseased cells and tissue to prevent over-activation of the pathway and reduce undesirable “on-target” “off tissue” toxicities. Additionally, the inertness of the VitoKine active moiety prior to protease activation will significantly decrease the potential antigen or target sink, and thus, prolong the in vivo half-life and result in improved biodistribution, bioavailability and therapeutic efficacy.

Core Innovation

The invention relates to a bioactivatable polypeptide drug construct comprising, in an N-to C-terminal direction (D1-D2-D3), a functional moiety D1 domain, a bioactivatable moiety D2 domain, and a concealing moiety D3 domain. The D1 domain is an Fc domain, the D2 domain is an interleukin-2 (IL-2) polypeptide, and the D3 domain is a cognate receptor/binding partner for IL-2 that conceals the activity of D2 until activated.

The construct includes peptide linkers L1 and L2 that connect D1-D2 and D2-D3, and each linker is selected from a protease cleavable peptide linker and a non-cleavable peptide linker. The system is designed so that D3 keeps D2 inert until activation at a disease site by disease-site upregulated proteases.

The platform addresses systemic on-target/off-tissue toxicity and antigen/target sink by limiting D2 activity through concealment until activation. It also emphasizes improved half-life, biodistribution, and developability, including reductions related to aggregation and expression improvements.

Claims Coverage

The independent claim coverage centers on a bioactivatable polypeptide drug construct with three inventive domain features and two linker features. The core inventive features are the N-to C-terminal D1-D2-D3 architecture and the function of D3 to conceal D2 activity until activated.

Overall, the claims are directed to an N-to-C D1-D2-D3 fusion where D1 is an Fc domain, D2 is an IL-2 polypeptide, and D3 is an IL-2 cognate receptor/binding partner that conceals D2 activity until activated, with L1 and L2 linkers that may be protease cleavable or non-cleavable.

Stated Advantages

Documented Applications