Compositions and methods for protein internalization
AssigneeLytica Therapeutics, Inc.
InventorsRida Mourtada, John Ernest Vallarta Bajacan, Daniel T. Cohen
Life of this patent
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Abstract
Provided herein are conjugates comprising a promoter peptide conjugated to an agent, such an antibody or antigen-binding fragment thereof. The promoter peptides promote the cellular internalization of the agent (e.g., the antibody or antigen-binding fragment thereof). The promoter peptides, when conjugated to an agent that binds a target protein (e.g., a receptor), can also promote internalization of the target protein into a cell. Also provided are methods of using the conjugates provided herein, e.g., for promoting the uptake of an antibody or antigen-binding fragment thereof into a cell, for promoting the uptake of a target protein into a cell.
Claims82
A method of promoting uptake of an agent into a cell, the method comprising contacting the cell with a conjugate, wherein the conjugate comprises a promoter peptide conjugated to the agent;
- and wherein the promoter peptide is a stapled peptide.
A method of promoting uptake of an agent into a cell, the method comprising contacting the cell with a conjugate, wherein the conjugate comprises a promoter peptide conjugated to the agent;
- and wherein the promoter peptide is a Magainin peptide.
A method of promoting uptake of an agent into a cell, the method comprising contacting the cell with a conjugate, wherein the conjugate comprises a promoter peptide conjugated to the agent;
- and wherein the promoter peptide comprises any one of SEQ ID NOs:
- 5-19.
A method of promoting uptake of a small molecule into a cell, the method comprising contacting the cell with a peptide-antibody conjugate (PAC), wherein the PAC comprises a promoter peptide conjugated to an antibody-drug conjugate (ADC);
- wherein ADC comprises the small molecule conjugated to an antibody or antigen-binding fragment thereof;
- and wherein the promoter peptide is a stapled peptide.
A method of promoting uptake of a small molecule into a cell, the method comprising contacting the cell with a peptide-antibody conjugate (PAC), wherein the PAC comprises a promoter peptide conjugated to an antibody-drug conjugate (ADC);
- wherein ADC comprises the small molecule conjugated to an antibody or antigen-binding fragment thereof;
- and wherein the promoter peptide is a Magainin peptide.
A method of promoting uptake of a small molecule into a cell, the method comprising contacting the cell with a peptide-antibody conjugate (PAC), wherein the PAC comprises a promoter peptide conjugated to an antibody-drug conjugate (ADC);
- wherein ADC comprises the small molecule conjugated to an antibody or antigen-binding fragment thereof;
- and wherein the promoter peptide comprises any one of SEQ ID NOs:
- 5-19.
A method of promoting uptake of a target protein into a cell, the method comprising contacting the cell with a conjugate, wherein the conjugate comprises a promoter peptide conjugated to an agent that binds the target protein;
- and wherein the promoter peptide is a stapled peptide.
A method of promoting uptake of a target protein into a cell, the method comprising contacting the cell with a conjugate, wherein the conjugate comprises a promoter peptide conjugated to an agent that binds the target protein;
- and wherein the promoter peptide is a Magainin peptide.
A method of promoting uptake of a target protein into a cell, the method comprising contacting the cell with a conjugate, wherein the conjugate comprises a promoter peptide conjugated to an agent that binds the target protein;
- and wherein the promoter peptide comprises any one of SEQ ID NOs:
- 5-19.
The method of any one of the preceding claims, wherein the antibody or antigen-binding fragment thereof is directed to a target protein expressed on a cancer cell.
The method of any one of the preceding claims, wherein the antibody is an antibody directed against CD38, or an antigen-binding fragment thereof.
The method of any one of the preceding claims, wherein the antibody is daratumumab, isatuximab, or mezagitamab.
The method of any one of the preceding claims, wherein the antibody is an antibody directed against CD20, CD33, or CD19, or an antigen-binding fragment thereof.
The method of any one of the preceding claims, wherein the antibody is obinutuzumab, vadastuximab, nimotuzumab, inebilizumab, or tafastimab.
The method of any one of the preceding claims, wherein the antibody is an antibody directed against HER2, or an antigen-binding fragment thereof.
The method of any one of the preceding claims, wherein the antibody is trastuzumab.
The method of any one of the preceding claims, wherein the antibody is an antibody directed against EGFR, or an antigen-binding fragment thereof.
The method of any one of the preceding claims, wherein the antibody is cetuximab.
The method of any one of the preceding claims, wherein the antibody or antigen-binding fragment thereof is a nanobody.
The method of any one of the preceding claims, wherein the antibody is a monoclonal antibody (mAb), or an antigen-binding fragment thereof.
The method of any one of the preceding claims, wherein the stapled peptide is a singly stapled, doubly stapled, or stitched peptide.
The method of any one of the preceding claims, wherein the stapled peptide is a stapled Magainin peptide.
The method of any one of the preceding claims, wherein the stapled peptide is a stapled Magainin II peptide.
The method of any one of the preceding claims, wherein the Magainin peptide is an unstapled Magainin peptide.
The method of any one of the preceding claims, wherein the Magainin peptide is an unstapled Magainin II peptide.
The method of any one of the preceding claims, wherein the promoter peptide comprises the amino acid sequence:
- (SEQ ID NO:
- 1)
- G X1 G Dap F X2 Dap Dap Dap Dap Dap F G Dap A X3 V
- G E X4 A Dap Dap,
- or a pharmaceutically acceptable salt thereof, wherein:
- X1, X2, X3, and X4 are each independently a natural or non-natural amino acid;
- optionally wherein X1 and X2 are connected via a crosslink, and X3 and X4 are connected via a crosslink;
- and
- wherein the amino acid sequence includes 0 to 11 amino acid substitutions, inclusive.
The method of any one of the preceding claims, wherein the promoter peptide comprises the amino acid sequence:
- (SEQ ID NO:
- 2)
- G X1 G Dap F X2 Dap Dap Dap Dap Dap FG Dap A X3 V
- G E X4 A Dap Dap G,
- or a pharmaceutically acceptable salt thereof, wherein:
- X1, X2, X3, and X4 are each independently a natural or non-natural amino acid;
- optionally wherein X1 and X2 are connected via a crosslink, and X3 and X4 are connected via a crosslink.
The method of any one of the preceding claims, wherein the promoter peptide is conjugated to the agent, the ADC, or the agent that binds a target protein, via a linker.
The method of any one of the preceding claims, wherein the cell is in a subject, and the method comprises administering to the subject an effective amount of the conjugate or PAC.
A peptide-antibody conjugate (PAC) selected from those in Table 2A, Table 2B, and Table 4.
A peptide comprising the amino acid sequence:
- (SEQ ID NO:
- 5)
- X5X6X7X5X6X7X5,
- or a pharmaceutically acceptable salt thereof, wherein:
- each X5 is independently selected from arginine, histidine, Dap, Dab, Orn, homo-lysine, homo-arginine, homo-histidine, 4-guanidino-phenylalanine, and 4-amino-phenylalanine;
- each X6 is independently selected from modified or unmodified phenylalanine, leucine, isoleucine, tryptophan, tyrosine, and norleucine;
- and
- each X7 is independently selected from alanine, valine, leucine, isoleucine, glycine, and serine.
A peptide-antibody conjugate (PAC) comprising a promoter peptide of any one of SEQ ID NOs:
- 5-19, or a pharmaceutically acceptable salt thereof, conjugated to an antibody or an antigen-binding fragment thereof.
A peptide-antibody conjugate (PAC) comprising a promoter peptide or a pharmaceutically acceptable salt thereof conjugated to an antibody or an antigen-binding fragment thereof, wherein the promoter peptide comprises any one of SEQ ID NOs:
- 142-174.
A stapled or unstapled peptide comprising any one of SEQ ID NOs:
- 142-174, or a pharmaceutically acceptable salt thereof.
Dependencies are inferred from the claim text.