Nectin-4 antibody conjugates and uses thereof
Inventors
Baum, Peter R. • DuBose, Robert • Odegard, Valerie • STEVENS, Brenda • Tan, Philip
Assignees
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Publication Number
US-11179473-B2
Publication Date
2021-11-23
Expiration Date
Abstract
The present disclosure provides conjugates of anti-Nectin-4 antibodies or antigen binding fragments thereof to a myeloid cell agonist, compositions comprising the conjugates, and methods of treating cancer with the conjugates. The present disclosure also provides for anti-Nectin-4 antibodies or antigen binding fragments thereof and method for using the antibodies or antigen binding fragments thereof in treating cancer.
Core Innovation
The invention relates to a myeloid cell agonist conjugate or a salt thereof represented by Formula (I), in which A is an anti-Nectin-4 antibody or an antigen-binding fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL). The VH comprises VH-CDR1, VH-CDR2, and VH-CDR3 with the amino acid sequences of SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3, and the VL comprises VL-CDR1 selected from SEQ ID NOS:4-6, VL-CDR2 with SEQ ID NO:7, and VL-CDR3 with SEQ ID NO:8.
In Formula (I), L is a linker and D comprises a TLR8 agonist, with n selected from 1 to 20 and z selected from 1 to 20. The conjugate couples an anti-Nectin-4 targeting component with a TLR8 myeloid cell agonist via a linker, and includes attachment-site concepts such as RX* attachment functionality. The disclosure also includes linker architectures with cleavable and non-cleavable linker designs.
The document further describes immune-stimulatory conjugate linkers that include enzymatically cleavable sugar moieties, hydrazone and acido-labile linkers, disulfide linkers, peptide linkers, self-immolative spacers such as PABA and PABC, and other degradable linkages. It also describes non-cleavable linker classes, including alkylene, polymeric/PEG/amide-based linkers, and Fleximer-type linker architectures for antibody-immune-stimulatory conjugates.
Claims Coverage
The consolidated claim coverage centers on one independent Formula (I) myeloid cell agonist conjugate (or salt) that links an anti-Nectin-4 antibody to a TLR8 agonist via a linker, with n and z each selected from 1 to 20. Across the provided claim sets, the inventive features recur as defined anti-Nectin-4 antibody CDR sequences, linker attachment chemistry, defined TLR8 agonist selection, linker architecture, parameter ranges for n and z, and an average TLR8 agonist-to-antibody ratio constraint in pharmaceutical compositions.
Anti-Nectin-4 antibody conjugated via linker to a TLR8 agonist
A myeloid cell agonist conjugate (or salt) represented by Formula (I), where A is an anti-Nectin-4 antibody or antigen-binding fragment, L is a linker, D comprises a TLR8 agonist, and n and z are each selected from 1 to 20.
Defined anti-Nectin-4 antibody variable region CDR sequences
The anti-Nectin-4 antibody comprises VH-CDR1, VH-CDR2, and VH-CDR3 with SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3, and VL-CDR1 selected from SEQ ID NOS:4-6, VL-CDR2 with SEQ ID NO:7, and VL-CDR3 with SEQ ID NO:8.
TLR8 agonist selected from defined compound set
The TLR8 agonist is selected from compounds 1.1-1.69 or a salt thereof.
Linker architecture with RX* attachment functionality
The linker includes RX* attachment options, where RX* is defined as a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to an antibody residue, with RX* indicating the attachment point to the antibody residue.
Conjugation parameters n and z
The Formula (I) conjugate uses n selected from 1 to 20 and z selected from 1 to 20.
Average TLR8 agonist-to-antibody ratio constraint in pharmaceutical composition
A pharmaceutical composition in which the conjugate has an average TLR8 agonist-to-antibody ratio within specified ranges, including about 2 to about 8, about 3 to about 8, about 3 to about 7, or about 3 to about 5.
The claim coverage consistently focuses on a Formula (I) conjugate of an anti-Nectin-4 antibody and a TLR8 agonist joined by a linker, with defined CDR sequences, RX* attachment chemistry, TLR8 agonist selection, n and z ranges, and, in some claim sets, an average TLR8 agonist-to-antibody ratio constraint.
Stated Advantages
Non-cleavable linkers may reduce bystander effects/nonspecific toxicity by providing more hydrophilic, less membrane-permeable released derivatives.
Non-cleavable linkers may improve circulation stability.
Enables release of the immune-stimulatory compound in targeted intracellular compartments.
Hydrazone/acido-labile linkers provide plasma stability with cleavage under acidic endosomal/lysosomal conditions.
Disulfide linkers enable reduction-triggered release in the intracellular reduction environment.
Enzymatically cleavable peptide and glycoside/linker designs enable cleavage by lysosomal enzymes to liberate the payload.
Self-immolative spacers enable liberation of the unmodified payload via 1,6-elimination.
Binds Nectin-4 cells.
Induces TNF-α from PBMCs.
Increases intra-tumoral chemokines and cytokines.
Can block TIGIT binding to Nectin-4.
Documented Applications
Treating Nectin-4-expressing cancers, including supported subcutaneous administration of pharmaceutical compositions containing the conjugates.
Antibody-immune-stimulatory conjugates using Fleximer-type linker architectures with intracellular release in endosomes and lysosomes.
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