TECHNICAL FIELD

This invention relates to compositions useful for imaging techniques, and more particularly to compounds that are useful for imaging HER3 using medical imaging, including positron emission tomography.

BACKGROUND

The receptor tyrosine kinase HER3 (ERBB3) is upregulated in response to targeted therapies in multiple cancers, including lung, breast and prostate cancers. Levels of HER3 expression are highly dynamic, making quantification by tissue sampling techniques such as biopsy potentially inaccurate. PET imaging, which permits global and serial imaging, may present a more robust method for HER3 quantification, improving HER3 diagnosis, facilitating improved clinical trials assessing HER3 expression, and, in the long term, providing accurate diagnosis of HER3 status to help diagnosis targeted therapy resistance.

SUMMARY

The present application provides, inter alia, a composition of Formula I:
A-B—C  I
wherein:

A comprises an imaging agent;

B is a linking group or a covalent bond; and

C is a polypeptide comprising from about 9 to about 75 amino acids, wherein the polypeptide comprises an amino acid sequence having at least 90% sequence identity to:


wherein:

refers to the bond between C and B;


refers to a disulfide bond between the cysteine groups;

X2is selected from the group consisting of L, L*, I, I*, P, P*, V, V*, G, and G*;

X3is selected from the group consisting of P, P*, L, L*, I, I*, V, V*, G, and G*;

X4is selected from the group consisting of T, T*, S, S*, C, C*, M, and M*;

X5is selected from the group consisting of any L-amino acid, any D-amino acid, and any non-natural amino acid;

X6is selected from the group consisting of any L-amino acid, any D-amino acid, and any non-natural amino acid;

X7is selected from the group consisting of R, R*, H, H*, K, K*, N, N*, Q, and Q*, and

X8is selected from the group consisting of S, S*, T, T*, C, C*, M, and M*,

wherein:

L* is a non-natural derivative of L;

I* is a non-natural derivative of I;

P* is a non-natural derivative of P;

V* is a non-natural derivative of V;

G* is a non-natural derivative of G;

T* is a non-natural derivative of T;

S* is a non-natural derivative of S;

C* is a non-natural derivative of C;

M* is a non-natural derivative of M;

R* is a non-natural derivative of R;

H* is a non-natural derivative of H;

K* is a non-natural derivative of K;

N* is a non-natural derivative of N; and

Q* is a non-natural derivative of Q.

In some embodiments, A comprises one or more imaging agents selected from the group consisting of a paramagnetic ion, an x-ray imaging agent, a fluorophore, and a radioisotope. In some embodiments, A comprises a radioisotope. In some embodiments, the radioisotope is suitable for PET imaging. In some embodiments, the radioisotope is selected from the group consisting of3H,11C,14C,18F,32P,35S,36Cl,51Cr,52Fe,57Co,58Co,59Fe,64Cu,67Cu,67Ga,68Ga,75Se,76Br,77Br,89Zr,90,99mTc,111In,123I,124I,125I,131I,152Eu,153Sm,166Ho,177Lu,186Re,188Re,201Tl,203Pb,210At,211At,212Bi,213Bi, and225Ac. In some embodiments, the radioisotope selected from the group consisting of3H,11C,14C18F,35S,52Fe,58Co,64Cu,68Ga,76Br,77Br,89Zr,111In,123I,124I,125I,131I,186Re,188Re, and201Tl. In some embodiments, A comprises68Ga.

In some embodiments, A further comprises a chelating agent. In some embodiments, the chelating agent is selected from the group consisting of 1,4,7-triazacyclononanetriacetic acid (NOTA), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), 1,4,7-triazacyclononane-1-glutaric acid-4,7-diacetic acid (NODAGA), ethylene diamine tetra-acetic acid (EDTA), diethylene triaminepentaacetic acid (DTPA), cyclohexyl-1,2-diaminetetraacetic acid (CDTA), ethyleneglycol-O,O′-bis(2-aminoethyl)-N,N,N′,N′-tetraacetic acid (EGTA), N,N-bis(hydroxybenzyl)-ethylenediamine-N,N′-diacetic acid (HBED), triethylene tetramine hexaacetic acid (TTHA), hydroxyethyidiamine triacetic acid (HEDTA), 1,4,8,11-tetraazacyclotetradecane-N,N′,N″,N′″-tetraacetic acid (TETA), 1,4,7,10-tetraaza-1,4,7,10-tetra-(2-carbamoyl methyl)-cyclododecane (TCMC), and 2,2′,2″-(2-(4-isothiocyanatobenzyl)-1,4,7-triazonane-1,4,7-triyl)triacetic acid (NOTA-NCS). In some embodiments, the chelating agent is selected from the group consisting of 1,4,7-triazacyclononanetriacetic acid (NOTA), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), 1,4,7-triazacyclononane-1-glutaric acid-4,7-diacetic acid (NODAGA), and 2,2′,2″-(2-(4-isothiocyanatobenzyl)-1,4,7-triazonane-1,4,7-triyl)triacetic acid (NOTA-NCS). In some embodiments, the chelating agent is 1,4,7-triazacyclononanetriacetic acid (NOTA) or 2,2′,2″-(2-(4-isothiocyanatobenzyl)-1,4,7-triazonane-1,4,7-triyl)triacetic acid (NOTA-NCS). In some embodiments, B is a linking group.

In some embodiments, B is a linking group comprising one or more C1-30alkyleneoxy groups, one or more independently selected amino acids, or any combination thereof. In some embodiments, B is a linking group comprising from about 1 to about 10 independently selected amino acids. In some embodiments, B is a linking group comprising a sequence having at least 90% sequence identity to:


wherein:

------ refers to the bond between B and A;

v refers to the bond between B and C;

X9is selected from the group consisting of beta A, 6-aminohexanoic acid, 8-aminooctanoic acid, and 2-(2-(2-aminoethoxy)ethoxy)acetic acid;

X10is selected from the group consisting of G, G*, A, A*, S, S*, P, P*, W, W*, Y, Y*, H, H*, T, T*, M, M*, N, N*, Q, and Q*;

X1is selected from the group consisting of G, G*, A, A*, S, S*, P, P*, W, W*, Y, Y*, H, H*, T, T*, M, M*, N, N*, Q, and Q*; and

X12is selected from the group consisting of G, G*, A, A*, S, S*, P, P*, W, W*, Y, Y*, H, H*, T, T*, M, M*, N, N*, Q, and Q*;

wherein:

G* is a non-natural derivative of G;

A* is a non-natural derivative of A;

S* is a non-natural derivative of S;

P* is a non-natural derivative of P;

W* is a non-natural derivative of W;

Y* is a non-natural derivative of Y;

H* is a non-natural derivative of H;

T* is a non-natural derivative of T;

M* is a non-natural derivative of M;

N* is a non-natural derivative of N; and

Q* is a non-natural derivative of Q.

In some embodiments, B is a linking group which is:


wherein:

------ refers to the bond between B and A; and

refers to the bond between B and C.

In some embodiments, C is a polypeptide comprising from about 15 to about 25 amino acids, wherein the polypeptide comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 12.

In some embodiments, X2is L or L*.

In some embodiments, X3is P or P*.

In some embodiments, X4is T or T*.

In some embodiments, X5is K or K*.

In some embodiments, X6is F or F*.

In some embodiments, X7is R or R*.

In some embodiments, X8is S or S*.

In some embodiments, the composition of Formula I is a composition of Formula Ia:


wherein


refers to a disulfide bond between the cysteine groups.

In some embodiments, the composition of Formula I is a composition of Formula Ib:


wherein A′ is a radioisotope; and


refers to a disulfide bond between the cysteine groups.

In some embodiments, the composition of Formula I is a composition of Formula Ic:


wherein


refers to a disulfide bond between the cysteine groups.

In some embodiments, the composition of Formula I is:


wherein


refers to a disulfide bond between the cysteine groups.

The present application further provides a composition of Formula II:
B—C

B comprises from about 1 to about 10 amino acids; and

C is a polypeptide comprising from about 9 to about 75 amino acids, wherein the polypeptide comprises an amino acid sequence having at least 90% sequence identity to:


wherein:

refers to the bond between C and B;


refers to a disulfide bond between the cysteine groups;

X2is selected from the group consisting of L, L*, I, I*, P, P*, V, V*, G, and G*;

X3is selected from the group consisting of P, P*, L, L*, I, I*, V, V*, G, and G*;

X4is selected from the group consisting of T, T*, S, S*, C, C*, M, and M*;

X5is selected from the group consisting of any L-amino acid, any D-amino acid, and any non-natural amino acid;

X6is selected from the group consisting of any L-amino acid, any D-amino acid, and any non-natural amino acid;

X7is selected from the group consisting of R, R*, H, H*, K, K*, N, N*, Q, and Q*, and

X8is selected from the group consisting of S, S*, T, T*, C, C*, M, and M*,

wherein:

L* is a non-natural derivative of L;

I* is a non-natural derivative of I;

P* is a non-natural derivative of P;

V* is a non-natural derivative of V;

G* is a non-natural derivative of G;

T* is a non-natural derivative of T;

S* is a non-natural derivative of S;

C* is a non-natural derivative of C;

M* is a non-natural derivative of M;

R* is a non-natural derivative of R;

H* is a non-natural derivative of H;

K* is a non-natural derivative of K;

N* is a non-natural derivative of N; and

Q* is a non-natural derivative of Q.

In some embodiments, B comprises a sequence having at least 90% sequence identity to:


wherein:

refers to the bond between B and C;

X9is selected from the group consisting of beta A, 6-aminohexanoic acid, 8-aminooctanoic acid, and 2-(2-(2-aminoethoxy)ethoxy)acetic acid;

X10is selected from the group consisting of G, G*, A, A*, S, S*, P, P*, W, W*, Y, Y*, H, H*, T, T*, M, M*, N, N*, Q, and Q*;

X11is selected from the group consisting of G, G*, A, A*, S, S*, P, P*, W, W*, Y, Y*, H, H*, T, T*, M, M*, N, N*, Q, and Q*; and

X12is selected from the group consisting of G, G*, A, A*, S, S*, P, P*, W, W*, Y, Y*, H, H*, T, T*, M, M*, N, N*, Q, and Q*;

wherein:

G* is a non-natural derivative of G;

A* is a non-natural derivative of A;

S* is a non-natural derivative of S;

P* is a non-natural derivative of P;

W* is a non-natural derivative of W;

Y* is a non-natural derivative of Y;

H* is a non-natural derivative of H;

T* is a non-natural derivative of T;

M* is a non-natural derivative of M;

N* is a non-natural derivative of N; and

Q* is a non-natural derivative of Q.

In some embodiments, B is:


whereinrefers to the bond between B and C

In some embodiments, C is a polypeptide comprising from about 15 to about 25 amino acids, wherein the polypeptide comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 1.

In some embodiments, X2is L or L*.

In some embodiments, X3is P or P*.

In some embodiments, X4is T or T*.

In some embodiments, X5is K or K*.

In some embodiments, X6is F or F*.

In some embodiments, X7is R or R*.

In some embodiments, X8is S or S*.

In some embodiments, the composition of Formula II is a composition of Formula IIa:


wherein


refers to a disulfide bond between the cysteine groups.

In some embodiments, the composition of Formula II is


wherein


refers to a disulfide bond between the cysteine groups.

In some embodiments, C is a polypeptide that binds HER3.

The present application further provides a pharmaceutical composition comprising a composition provided herein, and a pharmaceutically acceptable carrier.

The present application further provides a method of imaging cancer in a subject, the method comprising:

i) administering to the subject an effective amount of a composition provided herein (e.g., a composition of Formula I); and

ii) imaging the subject with a suitable imaging technique.

The present application further provides a method of treating a cancer in a subject, the method comprising:

i) administering to the subject an effective amount of a composition provided herein (e.g., a composition of Formula I);

ii) imaging the subject with a suitable imaging technique; and

iii) administering to the subject a therapeutically effective amount of one or more therapeutic agents.

The present application further provides a method of monitoring treatment of a cancer in a subject, the method comprising:

i) administering to the subject an effective amount of a composition provided herein (e.g., a composition of Formula I);

ii) imaging the subject with a suitable imaging technique; and

iii) administering to the subject a therapeutically effective amount of one or more therapeutic agents.

In some embodiments, the methods provided herein further comprise administering an additional effective amount of the composition to the subject after step iii). In some embodiments, the methods provided herein further comprise imaging the subject with a suitable imaging technique after step iii).

In some embodiments, the therapeutic agent is a chemotherapeutic agent. In some embodiments, the therapeutic agent is a HER3 inhibitor. In some embodiments, the therapeutic agent is selected from the group consisting of patritumab, MM-121, U3-1402, GSK2849330, neratinib, lumretuzumab, U3-1287, Sym013, AV-203, trastuzumab, pertuzumab, cetrorelix, enzalutamide, and erlotinib.

In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is selected from the group consisting of breast cancer, lung cancer, prostate cancer, gastric cancer, head and neck cancer, and ovarian cancer. In some embodiments, the prostate cancer is castration resistant prostate cancer.

In some embodiments, the imaging technique is selected from the group consisting of magnetic resonance (MR) imaging, positron emission tomography (PET) imaging, fluorescent imaging, single photon emission computed tomography (SPECT), luminescent imaging, or any combination thereof. In some embodiments, the imaging technique is positron emission tomography (PET) imaging.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Methods and materials are described herein for use in the present invention; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

