SSTR-TARGETED CONJUGATES AND PARTICLES AND FORMULATIONS THEREOF
Conjugates of an active agent such as DM1 attached to a targeting moiety, such as a somatostatin receptor binding moiety, via a linker, and particles comprising such conjugates have been designed. Such conjugates and particles can provide improved temporospatial delivery of the active agent, improved biodistribution and penetration in tumor, and/or decreased toxicity. Methods of making the conjugates, the particles, and the formulations thereof are provided. Methods of administering the formulations to a subject in need thereof are provided, for example, to treat or prevent cancer.
1 . A pharmaceutical composition comprising a conjugate and at least one excipient, wherein the conjugate comprises an active agent coupled to a somatostatin receptor (SSTR) targeting moiety by a linker, wherein the active agent is mertansine (DM1).
2 . The pharmaceutical composition of claim 1 , wherein the conjugate has a structure of:
3 . The pharmaceutical composition of claim 2 , wherein the conjugate has a concentration of between about 2.0-about 5.0 mg/mL.
4 . The pharmaceutical composition of claim 3 , wherein the conjugate has a concentration of about 2.5 mg/mL.
5 . The pharmaceutical composition of claim 2 , wherein the pH of the composition is between about 4.0 to about 5.0.
6 . The pharmaceutical composition of claim 5 , wherein the pH of the composition is between about 4.0 to about 4.8.
7 . The pharmaceutical composition of claim 6 , wherein the pH of the composition is about 4.0.
8 . The pharmaceutical composition of claim 6 , wherein the composition comprises acetate buffer.
9 . The pharmaceutical composition of claim 2 , wherein the composition further comprises mannitol.
10 . The pharmaceutical composition of claim 9 , wherein the mannitol has a concentration of between about 25 to about 75 mg/mL.
11 . The pharmaceutical composition of claim 10 , wherein the mannitol has a concentration of about 50 mg/mL.
12 . The pharmaceutical composition of claim 2 , wherein the composition further comprises polyoxyl 15 hydroxystearate.
13 . The pharmaceutical composition of claim 12 , wherein the polyoxyl 15 hydroxystearate has a concentration of between about 10 to about 50 mg/mL.
14 . The pharmaceutical composition of claim 13 , wherein the polyoxyl 15 hydroxystearate has a concentration of about 20 mg/mL.
15 . A method of treating tumor of a subject, comprising conducting a Somatostatin Analog Radioisotope Imaging (SARI) scanning on the subject and administering a pharmaceutical composition comprising a conjugate and at least one excipient to the subject if the SARI result is positive, wherein the conjugate comprises an active agent coupled to a somatostatin receptor (SSTR) targeting moiety by a linker, wherein the active agent is mertansine (DM1).
16 . The method of claim 15 , wherein the SARI scanning comprises using a radioisotope linked to a somatostatin analog.
17 . The method of claim 16 , wherein the radioisotope comprises 111 In, 68 Ga, or 99m Tc.
18 . The method of claim 16 , wherein the SARI scanning comprises using a 111 In pentetreotide.
19 . The method of claim 16 , wherein the SARI scanning comprises using 68 Ga derivatives of somatostatin analogs.
20 . The method of claim 19 , wherein the 68 Ga derivatives of somatostatin analogs comprise 68 Ga-DOTATATE or 68 Ga-DOTATOC.
21 . The method of claim 16 , wherein the SARI scanning is conducted with single-photon emission computed tomography (SPECT) or concurrent positron emission tomography (PET) and Computed tomography (CT).
22 . The method of claim 19 , further comprising administering at least one additional active agent.
23 . The method of claim 22 , wherein the additional active agent is a drug for treating nausea, vomiting, diarrhea, constipation, anemia, neutropenia, or a somatostatin analog.
24 . The method of claim 15 , wherein the tumor is a neuroendocrine tumor (NET).
25 . The method of claim 24 , wherein the tumor selected from the group consisting of gastroenteropancreatic (GEP), lung, prostate, and thymus neuroendocrine tumor.
26 . The method of claim 25 , wherein the tumor is small cell lung cancer (SCLC) or large cell neuroendocrine carcinoma (LCNEC) of the lung.
27 . The method of claim 15 , wherein the conjugate is Conjugate 57.
28 . The method of claim 27 , wherein the dosage of Conjugate 57 is at least about 0.016 mg/kg.
29 . The method of claim 27 , wherein the dosage of Conjugate 57 is at least about 1 mg, 2 mg, 4 mg, 8 mg, 12 mg, 18 mg, 24 mg, 30 mg, 36 mg, 42 mg, or 48 mg.
30 . The method of claim 27 , wherein the dosage of Conjugate 57 is about 25 mg.