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US 12,643,944 B2Granted
Antibody-payload conjugates with enhanced delivery domain and uses thereof
AssigneeIprogen Biotech Inc.
InventorsKeun Ho Lee, Leo Yen-Cheng Lin, Ranjani Vaidyanathan, Paula Lario
Life of this patent
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Abstract
The present invention provides a covalent conjugate. The conjugate includes an antibody or antibody derivative, at least two LL37-derived polypeptides, and a payload. The antibody or antibody derivative targets a cell that has phosphatidylserine in its outer leaflet. The payload includes: a small molecule cytotoxic drug of less than 3 kDa, or a plurality thereof; or a peptide or protein of less than 100 kDa. Uses and methods of using these covalent conjugates are also provided, related to enhancing delivery of the antibody/derivative or the payload, e.g. to enhance therapeutic or diagnostic effectiveness.
Claims13
A covalent conjugate comprising:
- an antibody that specifically binds to a cell surface epitope of a human cell, or an antibody derivative, the antibody derivative comprising:
- an antibody variable domain that specifically binds to the cell surface epitope of the human cell, and a hinge region coupling two heavy chains or two heavy chain fragments;
- a payload comprising:
- a small molecule drug of less than 3 kDa that is toxic to human cells, or a plurality of small molecule drugs that are each less than 3 kDa and which are toxic to human cells;
- or a peptide or protein of less than 100 kDa, wherein the peptide or protein comprises:
- a transcription factor, a bacterial toxin, a viral toxin, a protease, an RNAse, a DNAse, a proteolysis targeting chimera (PROTAC), or a fluorescent or colorimetric marker;
- and
- a first LL37-derived polypeptide and a second LL37-derived polypeptide, the first LL37-derived polypeptide and the second LL37-derived polypeptide each comprising an LL37-derived amino acid sequence or sequences, wherein each of the LL37-derived amino acid sequence or sequences independently comprise:
- SEQ ID NO:
- 14 (IGKEFKRIVQRIKDFLRNLVPRTES);
- or SEQ ID NO:
- 111 (SETRPVLNRLFDKIRQVIRKFEKGI);
- or a fragment of SEQ ID NO:
- 14 or 111 having consecutive deletions at either or both of the N- and C-termini up to a total deletion of at most 8 amino acids;
- or a plurality of fragments of SEQ ID NO:
- 14 and/or SEQ ID NO:
- 111, each fragment of the plurality of fragments independently having consecutive deletions at either or both of the N- and C-termini up to a total deletion of at most 10 amino acids;
- wherein each Lys and Arg residue in each fragment is independently substituted or not substituted with a conservative substitute amino acid residue selected from the group consisting of:
- Lys, Orn (omithine), DBu (2,4-diaminobutanoate), Dpr (2,3-diaminopropionate), Hyl (hydroxylysine), aHyl (allo-hydroxylysine), MeLys (6-N-methyllysine), Arg, Cit (citrulline), and 2-amino-3-guanidinopropionate;
- wherein 0, 1, 2, 3, 4 or 5 amino acid residues, selected from the group consisting of Gly, Asp, Glu, Asn, Gln, Ile, Leu, Val, Phe, Ser, Thr, Pro, and a combination thereof, in each fragment are each independently substituted with a conservative substitute amino acid residue selected from within its Group, X1, X2, X3, X4, X5, or X6 as defined below:
- (Group X1) Ala, Gly;
- (Group X2) Asp, Glu, bAad (3-aminoadipic acid), Apm (2-aminopimelic acid);
- (Group X3) Asn, Gln;
- (Group X4) Ile, Leu, Met, Val, Phe, Tyr, Trp, Abu (2-aminobutyric acid), Ahe (2-aminoheptanoic acid), alle (allo-isoleucine), Nva (norvaline), Nle (norleucine);
- (Group X5) Ser, Thr, Tyr;
- (Group X6) Pro, 3Hyp (3-hydroxyproline), 4Hyp (4-hydroxyproline);
- and
- wherein 0, 1 or 2 amino acid residues, selected from the group consisting of Lys, Arg, Gly, Asp, Glu, Asn, Gln, Ile, Leu, Val, Phe, Ser, Thr, Pro, and a combination thereof, in each fragment are each independently substituted with a non-conservative substitute a amino acid residue.
25 more elements
A covalent conjugate comprising:
- an antibody that specifically binds to a cell surface epitope of a human cell that has outer leaflet phosphatidylserine, or an antibody derivative, the antibody derivative comprising:
- an antibody variable domain that specifically binds to the cell surface epitope of the human cell, and a hinge region coupling two heavy chains or two heavy chain fragments;
- a payload comprising:
- a small molecule drug of less than 3 kDa that is toxic to human cells, or a plurality of small molecule drugs that are each less than 3 kDa and which are toxic to human cells;
- or a peptide or protein of less than 100 kDa, wherein the peptide or protein comprises:
- a transcription factor, a bacterial toxin, a viral toxin, a protease, an RNAse, a DNAse, a proteolysis targeting chimera (PROTAC), or a fluorescent or colorimetric marker;
- and
- a first LL37-derived polypeptide and a second LL37-derived polypeptide, the first LL37-derived polypeptide, the first LL37-derived polypeptide and the second LL37-derived polypeptide each comprising an LL37-derived amino acid sequence or sequences, wherein each of the LL37-derived amino acid sequence or sequences independently comprise:
- SEQ ID NO:
- 14 (IGKEFKRIVQRIKDFLRNLVPRTES);
- or SEQ ID NO:
- 111 (SETRPVLNRLFDKIRQVIRKFEKGI);
- or a fragment of SEQ ID NO:
- 14 or 111 having consecutive deletions at either or both of the N- and C-termini up to a total deletion of at most 8 amino acids;
- or a plurality of fragments of SEQ ID NO:
- 14 and/or SEQ ID NO:
- 111, each fragment of the plurality of fragments independently having consecutive deletions at either or both of the N- and C-termini up to a total deletion of at most 10 amino acids;
- wherein each Lys and Arg residue in each fragment is independently substituted or not substituted with a conservative substitute amino acid residue selected from the group consisting of:
- Lys, Orn (ornithine), DBu (2,4-diaminobutanoate), Dpr (2,3-diaminopropionate), Hyl (hydroxylysine), aHyl (allo-hydroxylysine), MeLys (6-N-methyllysine), Arg, Cit (citrulline), and 2-amino-3-guanidinopropionate;
- wherein 0, 1, 2, 3, 4 or 5 amino acid residues, selected from the group consisting of Gly, Asp, Glu, Asn, Gln, Ile, Leu, Val, Phe, Ser, Thr, Pro, and a combination thereof, in each fragment are each independently substituted with a conservative substitute amino acid residue selected from within its Group, X1, X1, X3, X4, X5, or X6 as defined below:
- (Group X1) Ala, Gly;
- (Group X2) Asp, Glu, bAad (3-aminoadipic acid), Apm (2-aminopimelic acid);
- (Group X3) Asn, Gln;
- (Group X4) Ile, Leu, Met, Val, Phe, Tyr, Trp, Abu (2-aminobutyric acid), Ahe (2-aminoheptanoic acid), alle (allo-isoleucine), Nva (norvaline), Nle (norleucine);
- (Group X5) Ser, Thr, Tyr;
- (Group X6) Pro, 3Hyp (3-hydroxyproline), 4Hyp (4-hydroxyproline);
- and
- wherein 0, 1 or 2 amino acid residues, selected from the group consisting of Lys, Arg, Gly, Asp, Glu, Asn, Gln, Ile, Leu, Val, Phe, Ser, Thr, Pro, and a combination thereof, in each fragment are each independently substituted with a non-conservative substitute amino acid residue.
25 more elements
A covalent conjugate comprising:
- an antibody that specifically binds to a cell surface epitope of a human cell, or an antibody derivative, the antibody derivative comprising:
- an antibody variable domain that specifically binds to the cell surface epitope of the human cell, and a hinge region coupling two heavy chains or two heavy chain fragments;
- a payload comprising:
- a small molecule drug of less than 3 kDa that is toxic to human cells, or a plurality of small molecule drugs that are each less than 3 kDa and which are toxic to human cells;
- or a peptide or protein of less than 100 kDa, wherein the peptide or protein comprises:
- a transcription factor, a bacterial toxin, a viral toxin, a protease, an RNAse, a DNAse, a proteolysis targeting chimera (PROTAC), or a fluorescent or colorimetric marker;
- and
- a first LL37-derived polypeptide and a second LL37-derived polypeptide, the first LL37-derived polypeptide, the first LL37-derived polypeptide and the second LL37-derived polypeptide each comprising an LL37-derived amino acid sequence or sequences, wherein each of the LL37-derived amino acid sequence or sequences independently comprise:
- SEQ ID NO:
- 14 (IGKEFKRIVQRIKDFLRNLVPRTES);
- or SEQ ID NO:
- 111 (SETRPVLNRLFDKIRQVIRKFEKGI);
- or a fragment of SEQ ID NO:
- 14 or 111 having consecutive deletions at either or both of the N- and C-termini up to a total deletion of at most 8 amino acids;
- or a plurality of fragments of SEQ ID NO:
- 14 and/or SEQ ID NO:
- 111, each fragment of the plurality of fragments independently having consecutive deletions at either or both of the N- and C-termini up to a total deletion of at most 10 amino acids;
- wherein each Lys and Arg residue in each fragment is independently substituted or not substituted with a conservative substitute amino acid residue selected from the group consisting of:
- Lys, Orn (ornithine), DBu (2,4-diaminobutanoate), Dpr (2,3-diaminopropionate), Hyl (hydroxylysine), aHyl (allo-hydroxylysine), MeLys (6-N-methyllysine), Arg, Cit (citrulline), and 2-amino-3-guanidinopropionate;
- wherein 0, 1, 2, 3, 4 or 5 amino acid residues, selected from the group consisting of Gly, Asp, Glu, Asn, Gln, Ile, Leu, Val, Phe, Ser, Thr, Pro, and a combination thereof, in each fragment are each independently substituted with a conservative substitute amino acid residue selected from within its Group, X1, X2, X3, X4, X5, or X6 as defined below:
- (Group X1) Ala, Gly;
- (Group X2) Asp, Glu, bAad (3-aminoadipic acid), Apm (2-aminopimelic acid);
- (Group X3) Asn, Gln;
- (Group X4) Ile, Leu, Met, Val, Phe, Tyr, Trp, Abu (2-aminobutyric acid), Ahe (2-aminoheptanoic acid), alle (allo-isoleucine), Nva (norvaline), Ne (norleucine);
- (Group X5) Ser, Thr, Tyr;
- (Group X6) Pro, 3Hyp (3-hydroxyproline), 4Hyp (4-hydroxyproline);
- wherein 0, 1 or 2 amino acid residues, selected from the group consisting of Lys, Arg, Gly, Asp, Glu, Asn, Gln, Ile, Leu, Val, Phe, Ser, Thr, Pro, and a combination thereof, in each fragment are each independently substituted with a non-conservative substitute amino acid residue;
- and
- wherein the human cell is:
- a cancer cell;
- a pathogen-infected cell;
- or an immune cell responsible for an autoimmune condition or disease.
29 more elements
Dependencies are inferred from the claim text.