Meditopes and meditope-binding antibodies and uses thereof

• US 8,962,804 B2
• Filed: 04/10/2012
• Issued: 02/24/2015
• Est. Priority Date: 10/08/2010
• Status: Active Grant

• Current Assignee: City of Hope
• Original Assignee: City of Hope
• Inventors: Williams, John C., Horne, David A., Ma, Yuelong, Chang, Heng Wei, Donaldson, Joshua Michael, Zer, Cindy, Bzymek, Krzysztof, Avery, Kendra Nicole, Xie, Jun
• Primary Examiner(s): Sang, Hong
• Application Number:
  US13/443,804
• Publication Number:
  US 20120301400A1
• Time in Patent Office: 1,050 Days
• US Class Current: 530/387.1
• CPC Class Codes: A61K 47/66 the modifying agent being a pre-targeting system involving a peptide or protein for targeting specific cells
• CPC Class Codes: A61K 47/6811 the drug being a protein or peptide, e.g. transferrin or bleomycin
• CPC Class Codes: A61K 47/6813 the drug being a peptidic cytokine, e.g. an interleukin or interferon
• CPC Class Codes: A61K 47/6851 the antibody targeting a determinant of a tumour cell
• CPC Class Codes: A61K 47/6877 the antibody being an immunoglobulin containing regions, domains or residues from different species
• CPC Class Codes: A61K 47/6897 Pre-targeting systems with two or three steps using antibody conjugates; Ligand-antiligand therapies
• CPC Class Codes: A61K 51/1087 the immunoglobulin comprises domains from different animal species, e.g. chimeric immunoglobulins
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• CPC Class Codes: C07K 16/18 against material from animals or humans
• CPC Class Codes: C07K 16/2863 against receptors for growth factors, growth regulators
• CPC Class Codes: C07K 16/32 against translation products of oncogenes
• CPC Class Codes: C07K 2299/00 Coordinates from 3D structures of peptides, e.g. proteins or enzymes
• CPC Class Codes: C07K 2317/34 Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
• CPC Class Codes: C07K 2317/40 characterized by post-translational modification
• CPC Class Codes: C07K 2317/55 Fab or Fab'
• CPC Class Codes: C07K 2317/567 Framework region [FR]
• CPC Class Codes: C07K 2317/622 Single chain antibody (scFv)
• CPC Class Codes: C07K 2317/92 Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Abstract

Antibodies and meditopes that bind to the antibodies are provided, as well as complexes, compositions and combinations containing the meditopes and antibodies, and methods of producing, using, testing, and screening the same, including therapeutic and diagnostic methods and uses.

Claims

1. An isolated meditope-enabled antibody or fragment thereof, comprising:

a heavy chain variable (VH) region, a heavy chain constant region (CH) or portion thereof, a light chain variable (VL) region comprising a threonine, serine, or aspartate at position 40, a residue other than glycine at position 41, a residue other than phenylalanine at position 83, and an aspartate or asparagine at position 85, according to Kabat numbering, and a light chain constant region (CL) or portion thereof, wherein

the meditope-enabled antibody is a meditope-enabled variant of a human or humanized template antibody, which variant contains a plurality of framework region (FR) modifications, according to Kabat numbering, compared to the template antibody, said FR modifications being only at positions selected from the group consisting of positions 8, 9, 10, 38, 39, 40, 41, 42, 43, 44, 45, 82, 83, 84, 85, 86, 87, 99, 100, 101, 102, 103, 104, and 105 of the light chain of said template antibody, according to Kabat numbering, and positions 6, 9, 38, 39, 40, 41, 42, 43, 44, 45, 84, 86, 87, 88, 89, 90, 91, 103, 104, 105, 106, 107, 108, 109, and 110 of the heavy chain of said template antibody, according to Kabat numbering; and

the meditope-enabled antibody or fragment binds to a meditope comprising a peptide of SEQ TD NO;

1, via a meditope binding site.

2. The meditope-enabled antibody or fragment of claim 1, wherein the VH region comprises a serine or proline at position 40 and an isoleucine at position 89, according to Kabat numbering.

3. The meditope-enabled antibody or fragment of claim 1, wherein the VL region further comprises an isoleucine or leucine at position 10, according to Kabat numbering, and the residue at position 83 is an isoleucine.

4. The meditope-enabled antibody or fragment of claim 1, wherein the VL region further comprises a valine or isoleucine at position 9 and a residue other than glutamine at position 100, according to Kabat numbering.

5. The meditope-enabled antibody or fragment of claim 1, wherein the VL region has a threonine at position 40, an asparagine at position 41, and an aspartate at position 85, according to Kabat numbering.

6. The meditope-enabled antibody or fragment of claim 1, wherein the VH region has a serine at position 40 and an isoleucine at position 89, according to Kabat numbering.

8. The meditope-enabled antibody or fragment of claim 1, wherein the meditope binds to the antibody or fragment with a dissociation constant of less than 10 μ

M, as measured by surface plasmon resonance (SPR).

9. The meditope-enabled antibody or fragment of claim 1, wherein the meditope binds to residues 40, 41, 83, and 85 of the VL region of the meditope-enabled antibody or fragment, according to Kabat numbering, and residues 39, 89, 10.5, and 108 of the VH region of the meditope-enabled antibody or fragment, according to Kabat numbering.

10. The meditope-enabled antibody or fragment of claim 1, comprising a light chain comprising the amino acid sequence set forth in SEQ ID NO:

9 and a heavy chain comprising the amino acid sequence set forth in SEQ ID NO;

6.

11. The meditope-enabled antibody or fragment of claim 1, wherein the FR modifications are at positions selected from the group consisting of positions 9, 10, 39, 40, 41, 42, 43, 83, and 85 of the light chain of said template antibody, according to Kabat numbering, and positions 40, 89, and 105 of the heavy chain of said template antibody, according to Kabat numbering.

13. The isolated meditope-enabled antibody or fragment of claim 1, wherein the VL region comprises the amino acid sequence of SEQ ID NO:

73.

14. The isolated meditope-enabled antibody or fragment of claim 1, wherein the VH region comprises the amino acid sequence of SEQ ID NO:

74.

15. The isolated meditope-enabled antibody or fragment of claim 1, wherein the VL region comprises the amino acid sequence of SEQ ID NO:

75.

16. The isolated meditope-enabled antibody or fragment of claim 1, wherein:

The VL region has a light chain framework (FR-L)1, an FR-L2, an FR-L3, and an FR-L4 of the light chain sequence set forth as SEQ ID NO;

9; and

the VH region has a heavy chain framework (FR-H) 1, an FR-H2, an FR-H3, and an FR-H4 of the heavy chain sequence set forth as SEQ ID NO;

6.

18. The meditope-enabled antibody or fragment thereof of claim 1, wherein:

the meditope-enabled antibody or fragment competes for antigen binding with, binds to the same epitope as an antibody or antigen-binding fragment thereof selected from the group consisting of abagovomab, abciximab, adalimumab, adecatumumab, alemtuzumab, altumomab, altumomab pentetate, anatumomab, anatumomab mafenatox, arcitumomab, atlizumab, basiliximab, bectumomab, ectumomab, belimumab, benralizumab, bevacizumab, brentuximab, canakinumab, capromab, capromab pendetide, catumaxomab, certolizumab, clivatuzumab tetraxetan, daclizumab, denosumab, eculizumab, edrecolomab, efalizumab, etaracizumab, ertumaxomab, fanolesomab, fontolizumab, gemtuzumab, girentuximab, golimumab, ibritumomab, igovomab, infliximab, ipilimumab, labetuzumab, mepolizumab, muromonab, muromonab-CD3, natalizumab, necitumumab nimotuzumab, ofatumumab, omalizumab, oregovomab, palivizumab, panitumumab, ranibizumab, rituximab, satumomab, sulesomab, ibritumomab, ibritumomab tiuxetan, tocilizumab, tositumomab, trastuzumab, ustekinumab, visilizumab, votumumab, zalutumumab, brodalumab, anrukinzumab, bapineuzumab, dalotuzumab, demcizumab, ganitumab, inotuzumab, mavrilimumab, moxetumomab pasudotox, rilotumumab, sifalimumab, tanezumab, tralokinumab, tremelimumab, and urelumab;

or

the meditope-enabled antibody or fragment specifically binds to an antigen selected from the group consisting of;

CA-125, glycoprotein (GP) IIb/IIIa receptor, TNF-alpha, CD52, TAG-72, Carcinoembryonic antigen (CEA), interleukin-6 receptor (IL-6R), IL-2, interleukin-2 receptor a-chain (CD25), CD22, B-cell activating factor, interleukin-5 receptor (CD125), VEGF, VEGF-A, CD30, IL-1beta, prostate specific membrane antigen (PSMA), CD3, EpCAM, EGF receptor (EGFR), MUC1, human interleukin-2 receptor, Tac, RANK ligand, C5R, or other complement proteins, CD11a, alpha-v beta-3 integrin, HER2, neu, CD15, CD20, Interferon gamma, CD33, CA-TX, CTLA-4, TL-5, CD3 epsilon, CAM, Alpha-4-integrin, IgE, IgE Fc region, an RSV antigen, F (or fusion) protein of respiratory syncytial virus (RSV), NCA-90 (granulocyte cell antigen), TL-6, GD2, GD3, IL-12, IL-23, IL-17, CTAA16.88, beta-amyloid, IGF-1 receptor (IGF-1R), delta-like ligand 4 (DLL4), alpha subunit of granulocyte macrophage colony stimulating factor receptor, hepatocyte growth factor, IFN-alpha, nerve growth factor, IL-13, CD326, PD-L1, CD47, and CD137.

20. The isolated meditope-enabled antibody of claim 1, wherein the VL region comprises an isoleucine or leucine at position 10, a threonine at position 40, an asparagine at position 41;

an isoleucine at position 83, and an aspartate at position 85, according to Kabat numbering; and

the VH region comprises an isoleucine at position 89, according to Kabat numbering.

21. The isolated meditope-enabled antibody of claim 1, wherein the VL region comprises an isoleucine or valine at position 9, an isoleucine or leucine at position 10, an arginine at position 39, a threonine at position 40, an asparagine at position 41, a glycine at position 42, a serine at position 43, an isoleucine at position 83, an aspartate at position 85, and an alanine at position 100;

according to Kabat numbering; and

the VH region comprises a serine at position 40 and an isoleucine at position 89, according to Kabat numbering.

22. The meditope-enabled antibody or fragment thereof of claim 1, wherein the VH region comprises an isoleucine, tyrosine, methionine, phenylalanine, or tryptophan at position 89, according to Kabat numbering.

7. The meditope-enabled antibody or fragment of claim wherein the peptide is a cyclic peptide.

12. An isolated meditope-enabled antibody or fragment thereof, comprising:

a heavy chain variable (VH) region, a heavy chain constant region (CH) or portion thereof, a light chain variable (VL) region comprising a threonine or serine at position 40, an asparagine at position 41, a residue other than phenylalanine at position 83, and an aspartate or asparagine at position 85, and a light chain constant region (CL) or portion thereof, wherein;

the meditope-enabled antibody is a meditope-enabled variant of a human or humanized template antibody, which variant contains a plurality of framework region (FR) modifications, according to Kabat numbering, compared to the template antibody, said FR modifications being only at positions selected from the group consisting of positions 8, 9, 10, 38, 39, 40, 41, 42, 43, 44, 45, 82, 83, 84, 85, 86, 87, 99, 100, 101, 102, 103, 104, and 105 of the light chain of said template antibody, according to Kabat numbering, and positions 6, 9, 38, 39, 40, 41, 42, 43, 44, 45, 84, 86, 87, 88, 89, 90, 91, 103, 104, 105, 106, 107, 108, 109, and 110 of the heavy chain of said template antibody, according to Kabat numbering; and

the antibody or fragment binds to a meditope comprising a peptide of SEQ ID NO;

1 via a meditope binding site and does not specifically bind to the epitope of EGFR that is specifically bound by cetuximab.

17. An isolated meditope-enabled antibody or fragment thereof, comprising:

a heavy chain variable (VH) region, a heavy chain constant region (CH) or portion thereof, a light chain variable (VL) region comprising a valine or isoleucine at position 9, a threonine, serine, or aspartate at position 40, a residue other than glycine at position 41, a residue other than phenylalanine at position 83, and an aspartate or asparagine at position 85, according to Kabat numbering, and a light chain constant region (CL) or portion thereof, wherein;

the meditope-enabled antibody is a meditope-enabled variant of a template antibody, wherein the template antibody is a human or humanized antibody and the meditope-enabled antibody contains a plurality of framework region (FR) modifications, according to Kabat numbering, compared to the template antibody, said FR modifications being only at positions selected from the group consisting of positions 8, 9, 10, 38, 39, 40, 41, 42, 43, 44, 45, 82, 83, 84, 85, 86, 87, 99, 100, 101, 102, 103, 104, and 105 of the light chain of said template antibody, according to Kabat numbering, and positions 6, 9, 38, 39, 40, 41, 42, 43, 44, 45, 84, 86, 87, 88, 89, 90, 91, 103, 104, 105, 106, 107, 108, 109, and 110 of the heavy chain of said template antibody according to Kabat numbering; and

the meditope-enabled antibody or fragment binds to a meditope comprising a peptide of SEQ ID NO;

1, via a meditope binding site and does not specifically bind to the epitope of EGFR that is specifically bound by cetuximab.

19. An isolated meditope-enabled antibody or fragment thereof, comprising:

a heavy chain variable (VH) region, a heavy chain constant region (CH) or portion thereof, a light chain variable (VL) region comprising an isoleucine or leucine at position 10, a threonine, serine, or aspartate at position 40, a residue other than glycine at position 41, an isoleucine at position 83, and an aspartate or asparagine at position 85, according to Kabat numbering, and a light chain constant region (CL) or portion thereof, wherein;

the meditope-enabled antibody is a meditope-enabled variant of a template antibody, wherein the template is a human or humanized antibody and the meditope-enabled antibody contains a plurality of framework region (FR) modifications, according to Kabat numbering, compared to the template antibody, said FR modifications being only at positions selected from the group consisting of positions 8, 9, 10, 38, 39, 40, 41, 42, 43, 44, 45, 82, 83, 84, 85, 86, 87, 99, 100, 101, 102, 103, 104, and 105 of the light chain of said template antibody, according to Kabat numbering, and positions 6, 9, 38, 39, 40, 41, 42, 43, 44, 45, 84, 86, 87, 88, 89, 90, 91, 103, 104, 105, 106, 107, 108, 109, and 110 of the heavy chain of said template antibody, according to Kabat numbering; and

the meditope-enabled antibody or fragment binds to a peptide meditope comprising SEQ TD NO;

1 via a meditope binding site and does not specifically bind to the epitope of EGFR that is specifically bound by cetuximab.