# US 11,433,148 B2 · IGF-1R monoclonal antibodies and uses thereof

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- Number: US 11,433,148 B2
- Document ID: US11433148B2
- Status: Granted
- Kind: B2
- Application number: 15/971,980
- Filed: 2018-05-04
- Published: 2019-03-21
- Granted: 2022-09-06
- Earliest claimed: 2017-05-05
- Assignees: Centre for Probe Development and Commercialization
- Applicants: Centre for Probe Development and Commercialization
- Inventors: Eric Steven Burak; John Richard Forbes; Matthew David Burr Moran; Ryan Wayne Simms; John Fitzmaurice Valliant; Alla Darwish
- Web page: https://patentgrep.com/patent/US11433148B2

## CPC

- A61K 51/0485: {Porphyrins, texaphyrins wherein the nitrogen atoms forming the central ring system complex the radioactive metal}
- A61K 51/1027: {against receptors, cell-surface antigens or cell-surface determinants}
- A61K 49/106: {the complex-forming compound being cyclic, e.g. DOTA}
- A61K 51/0482: {chelates from cyclic ligands, e.g. DOTA}
- A61K 51/1093: {conjugates with carriers being antibodies}
- A61K 51/1096: {radioimmunotoxins, i.e. conjugates being structurally as defined in A61K51/1093, and including a radioactive nucleus for use in radiotherapeutic applications}
- A61P 35/00: Antineoplastic agents
- C07K 16/26: against hormones {; against hormone releasing or inhibiting factors}
- C07K 16/2863: {against receptors for growth factors, growth regulators}
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)

## Abstract

The present invention relates to conjugates including a chelating moiety of a metal complex thereof and a therapeutic or targeting moiety, methods for their production, and uses thereof.

## Claims

### Claim 1

A compound having a structure of Formula I, or a pharmaceutically acceptable salt thereof:
A-L1-(L2)n-B Formula I
wherein A is a chelating moiety or a metal complex thereof;
L1 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted aryl or heteroaryl;
B is an antibody, or antigen binding fragment of the antibody, that specifically binds to IGF-1R, wherein the antibody or antigen binding fragment thereof is selected from the group consisting of figitumumab, cixutumumab, ganitumab, AVE1642, BIIB002, robatumumab, and teprotumumab;
n is 1;
each L2, independently, has the structure:
(—X1-L3-Z1—) Formula II
wherein X1 is C═O(NR1) or NR1, in which R1 is H or optionally substituted C1-C6 alkyl optionally substituted C1-C6 heteroalkyl, substituted aryl or heteroaryl;
L3 is optionally substituted C1-C50 alkyl or optionally substituted C1-C50 heteroalkyl; and
Z1 is CH2, C═O, C═S, OC═O, NR1C═O, or NR1; in which
R1 is H, optionally substituted C1-C6 alkyl, or pyrrolidine-2,5-dione,
wherein the chelating moiety is DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), DOTMA (1R,4R,7R,10R)-α,α′,α″,α′″-tetramethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, DOTAM (1,4,7,10-tetrakis(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane), DOTPA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra propionic acid), DO3AM-acetic acid (2-(4,7,10-tris(2-amino-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetic acid), DOTA-GA anhydride (2,2′,2″-(10-(2,6-dioxotetrahydro-2H-pyran-3-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid, DOTP (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra(methylene phosphonic acid)), DOTMP (1,4,6,10-tetraazacyclodecane-1,4,7,10-tetramethylene phosphonic acid, DOTA-4AMP (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis(acetamido-methylenephosphonic acid), CB-TE2A (1,4,8,11-tetraazabicyclo[6.6.2]hexadecane-4,11-diacetic acid), NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid), NOTP (1,4,7-triazacyclononane-1,4,7-tri(methylene phosphonic acid), TETPA (1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetrapropionic acid), TETA (1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetra acetic acid), HEHA (1,4,7,10,13,16-hexaazacyclohexadecane-1,4,7,10,13,16-hexaacetic acid), PEPA (1,4,7,10,13-pentaazacyclopentadecane-N,N′,N″,N′″, N″″-pentaacetic acid), H4octapa (N,N′-bis(6-carboxy-2-pyridylmethyl)-ethylenediamine-N,N′-diacetic acid), H2dedpa (1,2-[[6-(carboxy)-pyridin-2-yl]-methylamino]ethane), H6phospa (N,N′-(methylenephosphonate)-N,N′-[6-(methoxycarbonyl)pyridin-2-yl]-methyl-1,2-diaminoethane), TTHA (triethylenetetramine-N,N,N′,N″,N′″, N′″-hexaacetic acid), DO2P (tetraazacyclododecane dimethanephosphonic acid), HP-DO3A (hydroxypropyltetraazacyclododecanetriacetic acid), EDTA (ethylenediaminetetraacetic acid), Deferoxamine, DTPA (diethylenetriaminepentaacetic acid), DTPA-BMA (diethylenetriaminepentaacetic acid-bismethylamide), or porphyrin.

### Claim 2 (depends on 1)

The compound of claim 1, wherein the chelating moiety is selected from the group consisting of DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), DOTMA (1R,4R,7R,10R)-α,α′,α″,α′″-tetramethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, DOTAM (1,4,7,10-tetrakis(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane), DOTPA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra propionic acid), DO3AM-acetic acid (2-(4,7,10-tris(2-amino-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetic acid), DOTA-GA anhydride (2,2′,2″-(10-(2,6-dioxotetrahydro-2H-pyran-3-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid, DOTP (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra(methylene phosphonic acid)), and DOTA-4AMP (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis(acetamido-methylenephosphonic acid).

### Claim 3 (depends on 2)

The compound of claim 2, wherein the structure of Formula I is:
wherein Y1 is —CH2OCH2(L2)n-B, C═O(L2)n-B, or C═S(L2)n-B and Y2 is —CH2CO2H; or
wherein Y1 is H and Y2 is L1-(L2)n-B,
L2, independently,
(-Xi-L3-Zi-) Formula II
wherein X1 is C═O(NR′) or NR1, R1 is H or optionally substituted C1-C6 alkyl optionally substituted C1-C6 heteroalkyl, substituted aryl or heteroaryl; L3 is optionally substituted C1-C50 alkyl or optionally substituted C1-C50 heteroalkyl; and Z1 is CH2, C═O, C═S, OC═O, NR1C═O, or NR1; R1 is H, optionally substituted C1-C6 alkyl, or pyrrolidine-2,5-dione, wherein the chelating moiety is DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), DOTMA (1R,4R,7R,10R)-a, a′, a″, a′″-tetramethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, DOTAM (1,4,7,10-tetrakis(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane), DOTPA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra propionic acid), DO3AM-acetic acid (2-(4,7,10-tris(2-amino-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetic acid), DOTA-GA anhydride (2,2′,2″-(10-(2,6-dioxotetrahydro-2H-pyran-3-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid, DOTP (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra(methylene phosphonic acid)), DOTMP (1,4,6,10-tetraazacyclodecane-1,4,7,10-tetramethylene phosphonic acid, DOTA-4AMP (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis(acetamido-methylenephosphonic acid), CB-TE2A (1,4,8,11-tetraazabicyclo[6.6.2]hexadecane-4,11-diacetic acid), NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid), NOTP (1,4,7-triazacyclononane-1,4,7-tri(methylene phosphonic acid), TETPA (1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetrapropionic acid), TETA (1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetra acetic acid), HEHA (1,4,7,10,13,16-hexaazacyclohexadecane-1,4,7,10,13,16-hexaacetic acid), PEPA (1,4,7,10,13-pentaazacyclopentadecane-N,N′,N″,N′″, N″″-pentaacetic acid), H4octapa (N,N′-bis(6-carboxy-2-pyridylmethyl)-ethylenediamine-N,N′-diacetic acid), H2dedpa (1,2-[[6-(carboxy)-pyridin-2-yl]-methylamino]ethane), H6phospa (N,N′-(methylenephosphonate)-N,N′-[6-(methoxycarbonyl)pyridin-2-yl]-methyl-i,2-diaminoethane), TTHA (triethylenetetramine-N,N,N′,N″,N′″, N′″-hexaacetic acid), DO2P (tetraazacyclododecane dimethanephosphonic acid), HP-DO3A (hydroxypropyltetraazacyclododecanetriacetic acid), EDTA (ethylenediaminetetraacetic acid), Deferoxamine, DTPA (diethylenetriaminepentaacetic acid), DTPA-BMA (diethylenetriaminepentaacetic acid-bismethylamide), or porphyrin;
n is 1;
B is an antibody, or antigen binding fragment of the antibody, that specifically binds to IGF-1R, wherein the antibody or antigen binding fragment thereof is selected from the group consisting of figitumumab, cixutumumab, ganitumab, AVE1642, BIIB002, robatumumab, and teprotumumab; and
L1 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted aryl or heteroaryl.

### Claim 4 (depends on 1)

The compound of claim 1, wherein L1 is:
wherein R2 is hydrogen or —CO2H.

### Claim 5 (depends on 1)

The compound of claim 1, wherein the metal of said metal complex is selected from the group consisting of Bi, Pb, Y, Mn, Cr, Fe, Co, Zn, Ni, Tc, In, Ga, Cu, Re, a lanthanide, and an actinide, or
the metal of said metal complex is a radionuclide selected from the group consisting of 47Sc, 55Co, 60Cu, 61Cu, 62Cu, 64Cu, 67Cu, 66Ga, 67Ga, 68Ga, 82Rb, 86Y, 87Y, 90Y, 97Ru, 99mTc, 105Rh 109Pd, 111In, 117mSn, 149Pm, 49Tb, 153Sm, 177Lu, 186Re, 188Re, 199Au, 201Tl, 203Pb, 212Pb, 212Bi, 213Bi, 225Ac, and 227Th.

### Claim 6 (depends on 3)

The compound of claim 3, wherein Y1 is H.

### Claim 7 (depends on 1)

The compound of claim 1 wherein X1 is C═O(NR1) and R1 is H.

### Claim 8 (depends on 1)

The compound of claim 1, wherein Z1 is —CH2.

### Claim 9 (depends on 1)

The compound of claim 1, wherein the compound is:
wherein variable B is as defined in claim 1.

### Claim 10 (depends on 5)

The compound of claim 5, wherein the metal is a radionuclide.

### Claim 11 (depends on 10)

The compound of claim 10, wherein the radionuclide is In111.

### Claim 12 (depends on 10)

The compound of claim 10, wherein the radionuclide is Ga68.

### Claim 13 (depends on 1)

The compound of claim 1, wherein the metal is an alpha-emitting radionuclide.

### Claim 14 (depends on 13)

The compound of claim 13, wherein the alpha-emitting radionuclide is Ac225.

### Claim 15 (depends on 1)

The compound of claim 1 wherein said antibody, or antigen-binding fragment thereof comprises a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 4.

### Claim 16 (depends on 1)

The compound of claim 1, wherein said antibody, or antigen-binding fragment thereof comprises a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 8.

### Claim 17 (depends on 1)

The compound of claim 1, wherein said antibody, or antigen-binding fragment thereof is AVE1642.

### Claim 18 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

### Claim 19 (depends on 1)

A method of radiation treatment planning and/or radiation treatment, comprising administering to a subject in need thereof a diagnostically effective amount of a compound of claim 1 and/or administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1, wherein the compound in each occurrence comprises a radionuclide.

### Claim 20 (depends on 1, 13)

A method of treating cancer, the method comprising administering to a subject in need thereof a first dose of a compound of claim 13 in an amount effective for treating cancer, followed by administering a second dose of a compound of claim 1, wherein the metal of said metal complex is selected from the group consisting of Bi, Pb, Y, Mn, Cr, Fe, Co, Zn, Ni, Tc, In, Ga, Cu, Re, a lanthanide, and an actinide; or
The metal of said metal complex is a radionuclide selected from the group consisting of 47Sc, 55Co, 60Cu, 61Cu, 62Cu, 64Cu, 67Cu, 66Ga, 67Ga, 68Ga, 82Rb, 86Y, 87Y, 90Y, 97Ru, 99mTc, 105Rh, 109Pd, 111In, 117mSn, 149Pm, 149Tb, 153Sm, 177Lu, 186Re, 188Re, 199Au, 201T1, 203Pb, 212Pb, 212Bi, 213Bi, 225Ac, and 227Th.

### Claim 21 (depends on 20)

The method of claim 20, wherein the compound administered in the first dose and the compound administered in the second dose are the same.

### Claim 22 (depends on 20)

The method of claim 20, wherein the compound administered in the first dose and the compound administered in the second dose are different.

### Claim 23 (depends on 20)

The method of claim 20, wherein the cancer is a solid tumor or hematologic (liquid) cancer.

### Claim 24 (depends on 23)

The method claim 23, wherein the cancer is breast cancer, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, head and neck cancer, prostate cancer, colorectal cancer, sarcoma, adrenocortical carcinoma, Ewing's Sarcoma, multiple myeloma, or acute myeloid leukemia.

### Claim 25 (depends on 24)

The method of claim 24, further comprising administering an antiproliferative agent, radiation sensitizer, an immunoregulatory or immunomodulatory agent.

### Claim 26 (depends on 25)

The method of claim 25, wherein the compound and the antiproliferative agent or radiation sensitizer are administered within 28 days of each other.

### Claim 27 (depends on 25)

The method of claim 25, wherein the compound and the immunoregulatory or immunomodulatory agent are administered within 90 days of each other.

### Claim 28 (depends on 1)

The compound of claim 1, wherein L3 is C5-C20 polyethylene glycol.

### Claim 29 (depends on 1)

The compound of claim 1, wherein said antibody, or antigen-binding fragment thereof comprises a light chain variable domain comprising at least one complementarity determining region (CDR) selected from:
(a) CDR-L1 comprising the amino acid sequence of SEQ ID NO:1;
(b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 2; and
(c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 3.

### Claim 30 (depends on 29)

The compound of claim 29, wherein said antibody, or antigen-binding fragment thereof comprises a light chain variable domain comprising at least two of said CDRs.

### Claim 31 (depends on 30)

The compound of claim 30, wherein said antibody, or antigen-binding fragment thereof comprises a light chain variable domain comprising all three said CDRs.

### Claim 32 (depends on 1)

The compound of claim 1, wherein said antibody, or antigen-binding fragment thereof comprises a heavy chain variable domain comprising at least one CDR selected from:
(a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 5;
(b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 6; and
(c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 7.

### Claim 33 (depends on 32)

The compound of claim 32, wherein said antibody, or antigen-binding fragment thereof comprises a heavy chain variable domain comprising at least two of said CDRs.

### Claim 34 (depends on 33)

The compound of claim 33, wherein said antibody, or antigen-binding fragment thereof comprises a heavy chain variable domain comprising all three said CDRs.

### Claim 35 (depends on 1)

The compound of claim 1, wherein said antibody, or antigen-binding fragment thereof comprises a heavy chain variable domain and a light chain variable domain, comprising at least one CDR selected from:
(a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 1;
(b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 2;
(c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 3;
(d) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 5;
(e) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 6; and
(f) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 7.

### Claim 36 (depends on 35)

The compound of claim 35, wherein said antibody, or antigen-binding fragment thereof comprises a heavy chain variable domain and a light chain variable domain, comprising at least two of said CDRs.

### Claim 37 (depends on 36)

The compound of claim 36, wherein said antibody, or antigen-binding fragment thereof comprises a heavy chain variable domain and a light chain variable domain, comprising at least three of said CDRs.

### Claim 38 (depends on 37)

The compound of claim 37, wherein said antibody, or antigen-binding fragment thereof comprises a heavy chain variable domain and a light chain variable domain, comprising at least four of said CDRs.

### Claim 39 (depends on 38)

The compound of claim 38, wherein said antibody, or antigen-binding fragment thereof comprises a heavy chain variable domain and a light chain variable domain, comprising at least five of said CDRs.

### Claim 40 (depends on 39)

The compound of claim 39, wherein said antibody, or antigen-binding fragment thereof comprises a heavy chain variable domain and a light chain variable domain, comprising all six said CDRs.