Cytokine-based bioactivatable drugs and methods of uses thereof
Inventors
Li, Yue-Sheng • Rui, Lingyun • Xu, Jing
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-11634467-B2
Publication Date
2023-04-25
Expiration Date
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 arranged in an N- to C-terminal direction as D1-D2-D3. The D1 domain is a functional Fc domain, the D2 domain is an interleukin-15 (IL-15) polypeptide, and the D3 domain is an IL-15 cognate receptor/binding partner that conceals the activity of D2 until activated.
In the construct, D1 is attached to D2 by a peptide linker (L1), and D2 is attached to D3 by a peptide linker (L2). Each linker is selected from protease cleavable peptide linkers and non-cleavable peptide linkers, supporting bioactivatable behavior while maintaining the D1-D2-D3 arrangement.
The disclosed construct specifies sequence-selected embodiments for the domains, with the Fc domain selected from SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 156, and SEQ ID NOS: 166-168, the IL-15 polypeptide selected from SEQ ID NOS: 2-3, and the IL-15 cognate receptor/binding partner selected from SEQ ID NOS: 4-5. The platform is described as a cytokine-based bioactivatable drug construct with higher-order domain formats in terms of monomers and dimers.
Claims Coverage
The independent claim covers a bioactivatable polypeptide drug construct with a three-domain D1-D2-D3 architecture and specifies an Fc-based D1, an IL-15-based D2, an IL-15 cognate receptor/binding partner D3 that conceals D2 activity, and peptide linkers L1 and L2 that are protease cleavable and/or non-cleavable. Dependent claims further narrow the construct by constraining linker protease-cleavability combinations, fixing specific SEQ ID NO assignments for D1/D2/D3, specifying particular linker sequence identities, constraining monomer/dimer formats, and optionally adding a pharmaceutical composition including the construct with a pharmaceutically acceptable carrier.
Three-domain bioactivatable polypeptide drug construct in N- to C-terminal direction (D1-D2-D3)
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, wherein D3 conceals the activity of D2 until activated.
Fc-based D1 domain sequence selection
The D1 domain is an Fc domain comprising an amino acid sequence selected from the group consisting of the amino acid sequences set forth in SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 156, and SEQ ID NOS: 166-168.
IL-15 D2 domain sequence selection
The D2 domain is an interleukin-15 (IL-15) polypeptide comprising an amino acid sequence selected from the group consisting of the amino acid sequences set forth in SEQ ID NOS: 2-3.
IL-15 cognate receptor/binding partner D3 sequence selection
The D3 domain is a cognate receptor/binding partner for IL-15 comprising an amino acid sequence selected from the group consisting of the amino acid sequences set forth in SEQ ID NOS: 4-5.
Protease cleavable and/or non-cleavable peptide linkers L1 and L2
D1 is attached to D2 by a peptide linker (L1) selected from the group consisting of a protease cleavable peptide linker and a non-cleavable peptide linker, and D2 is attached to D3 by a peptide linker (L2) selected from the group consisting of a protease cleavable peptide linker and a non-cleavable peptide linker.
Overall, the claim coverage is grounded in a D1-D2-D3 bioactivatable cytokine construct where IL-15-based D2 activity is concealed by an IL-15 cognate receptor/binding partner D3 until activation, with an Fc-based D1 domain and peptide linkers (L1 and L2) that are protease cleavable and/or non-cleavable.
Stated Advantages
D3 conceals the activity of D2 until activated.
The construct is described as concealing IL-15 activity in the VitoKine format with restoration after protease cleavage.
Reduced systemic IL-15 effects in healthy mice are described.
Minimized systemic lymphocyte proliferation is described for protease-activatable VitoKines.
Documented Applications
Cancer-related therapeutic activity is described, including anti-metastatic activity in a CT26 pulmonary metastasis model and established CT26 tumor growth.
Autoimmune/inflammatory therapeutic indications are described.
Viral therapeutic indications are described.
Therapeutic uses are described for cancer, autoimmune, inflammatory, and viral infections including HIV, including combination therapies.
Interested in licensing this patent?