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CN-122029200-A - Compositions and methods for enhancing the effects of Trop-2 specific therapeutics

CN122029200ACN 122029200 ACN122029200 ACN 122029200ACN-122029200-A

Abstract

A method of treating a subject in need thereof is disclosed, the method comprising applying an alternating electric field to a target site of the subject in need thereof at a frequency over a period of time, and administering a Trop-2 specific therapeutic agent to the subject in need thereof. The disclosed methods can also enhance the efficacy of Trop-2 specific therapeutics, prolong the progression-free survival of cancer subjects, reduce tumor growth, and increase the killing effect of cancer cells.

Inventors

  • T. Voloshen Serra
  • R. Kelly

Assignees

  • 诺沃库勒有限责任公司

Dates

Publication Date
20260512
Application Date
20241011
Priority Date
20231012

Claims (15)

  1. 1. A composition comprising a trophoblast cell surface antigen-2 (Trop-2) specific therapeutic for use in a method of treating a subject in need thereof, the method comprising: a) Applying an alternating electric field to a target site of the subject in need thereof, and B) Administering the Trop-2 specific therapeutic to the subject in need thereof.
  2. 2. A composition comprising a trophoblast cell surface antigen-2 (Trop-2) specific therapeutic for use in a method of enhancing the efficacy of a Trop-2 inhibitor in a subject in need thereof, the method comprising: a) Applying an alternating electric field to a target site of the subject in need thereof, and B) Administering the Trop-2 specific therapeutic to the subject in need thereof.
  3. 3. The composition of any one of the preceding claims, wherein a subject in need thereof has cancer.
  4. 4. The composition of claim 3, wherein the cancer is lung cancer, breast cancer, cervical cancer, colon cancer, gastric cancer, renal cancer, prostate cancer, thyroid cancer, glioblastoma, mesothelioma, pancreatic cancer, non-small cell lung cancer, ovarian cancer, liver cancer.
  5. 5. The composition of any one of the preceding claims, wherein the target site comprises one or more cancer cells.
  6. 6. The composition of claim 5, wherein the one or more cancer cells are lung cancer cells, breast cancer cells, cervical cancer cells, colon cancer cells, gastric cancer cells, kidney cancer cells, prostate cancer cells or thyroid cancer cells, glioblastoma cancer cells, mesothelioma cancer cells, pancreatic cancer cells, non-small cell lung cancer cells, ovarian cancer cells, liver cancer cells.
  7. 7. The composition of any one of claims 5 to 6, wherein one or more cancer cells are killed.
  8. 8. A method of killing cancer cells, the method comprising: a) Applying an alternating electric field to a population of cells comprising one or more cancer cells, and B) Contacting the population of cells with a trophoblast cell surface antigen-2 (Trop-2) specific therapeutic agent.
  9. 9. The composition of claim 9, wherein the population of cells is in vitro or in a subject.
  10. 10. The composition of any one of the preceding claims, wherein the Trop-2 specific therapeutic is an antibody-drug conjugate, preferably wherein the antibody-drug conjugate is golian Sha Tuozhu mab, PF-06664178, daptomidine Shan Kangde Lu Tikang, JS108, SKB264, or STI-3258.
  11. 11. The composition of any one of the preceding claims, wherein the alternating electric field is applied before, after, or simultaneously with the Trop-2 specific therapeutic agent.
  12. 12. The composition of any one of the preceding claims, wherein the Trop-2 specific therapeutic is administered intravenously, intratumorally, intracranially, intraventricular, intrathecally, epidurally, endovascularly, intraarterially, intramuscularly, subcutaneously, intraperitoneally, orally, intranasally, topically, via intratumoral injection, or via inhalation.
  13. 13. The composition of any one of the preceding claims, wherein the Trop-2 specific therapeutic inhibits IGF-1 signaling or blocks IGF-1 binding to its receptor IGF-1R.
  14. 14. The composition of any of the preceding claims, wherein the alternating electric field has a frequency between 50kHz and 1 MHz.
  15. 15. The composition of any of the preceding claims, wherein the alternating electric field has a field strength between 0.5V/cm RMS and 10V/cm RMS.

Description

Compositions and methods for enhancing the effects of Trop-2 specific therapeutics Cross Reference to Related Applications The present application claims the benefit of U.S. provisional patent application No. 63/589,757 filed on 10/12 of 2023, which is incorporated herein by reference in its entirety. Technical Field Trop-2 is highly suitable as a diagnostic and therapeutic target, particularly for antibody-based therapies, due to its broad expression in cancer cells and low expression levels in most normal tissues. However, related toxicities have been reported in connection with the role of Trop-2 in healthy tissues IGF-1 binds to Trop-2, resulting in modulation of IGF-1 signaling. Trop-2 can also bind to IGF-1 receptor (IGF-1R), thereby blocking IGF-1 signaling and playing a key role in cell growth, differentiation, transformation and metastasis. Trop-2 overexpression appears to be associated with increased risk of metastasis in patients affected by a variety of cancers (oral squamous carcinoma, thyroid carcinoma, partial esophageal carcinoma, gastric carcinoma, colorectal carcinoma, pancreatic carcinoma, ovarian carcinoma, uterine carcinoma, cervical carcinoma, prostate carcinoma and bladder carcinoma). Overexpression of Trop-2 has also been associated with increased tumor growth, proliferation and metastasis in a variety of epithelial cancers (i.e., head and neck, thyroid, lung, gastrointestinal, breast, renal, and gynecological cancers and gliomas). Upregulation of Trop-2 has been found to promote tumor growth, while inhibition of Trop2 prevents cell proliferation and invasion. Disclosure of Invention A method of treating a subject in need thereof is disclosed, the method comprising applying an alternating electric field to a target site of the subject in need thereof at a frequency over a period of time, and administering a Trop-2 specific therapeutic agent to the subject in need thereof. A method of enhancing the efficacy of a Trop-2 specific therapeutic agent in a subject in need thereof is disclosed, the method comprising applying an alternating electric field to a target site of the subject in need thereof at a frequency over a period of time, and administering the Trop-2 specific therapeutic agent to the subject in need thereof. A method of extending progression free survival of a cancer subject is disclosed, the method comprising applying an alternating electric field to a target site of the subject at a frequency over a period of time, and administering a Trop-2 specific therapeutic agent to the subject. A method of reducing tumor growth in a subject in need thereof is disclosed, the method comprising applying an alternating electric field to a target site of the subject in need thereof at a frequency over a period of time, and administering a Trop-2 inhibitor to the subject in need thereof. A method of killing cancer cells is disclosed, the method comprising applying an alternating electric field to a population of cells comprising one or more cancer cells at a frequency over a period of time, and contacting the population of cells with a trophoblast cell surface antigen-2 (Trop-2) inhibitor. Additional advantages of the disclosed methods and compositions will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the disclosed methods and compositions. The advantages of the disclosed methods and compositions will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed. Drawings The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several embodiments of the disclosed methods and compositions and together with the description, serve to explain the principles of the disclosed methods and compositions. Fig. 1 shows Trop2 signaling pathways. FIG. 2 shows the upregulation of IGF-1 levels following TTField treatment. Fig. 3 shows that TTField in combination with golian Sha Tuozhu mab synergistically inhibited a549 cell growth. The results were analyzed using a one-way ANOVA in combination with a multiple comparison test of Tukey. * p <0.05, < p < 0.01, < p < 0.001 and p < 0.0001. Fig. 4 shows that TTField in combination with golian Sha Tuozhu mab synergistically enhanced the overall effect in a549 cells. The results were analyzed using a T-test. * p <0.05, < p < 0.01, < p < 0.001 and p < 0.0001. Fig. 5 shows that TTField in combination with golian Sha Tuozhu mab enhances the apoptotic effect in a549 cells. AnnexinV-7 AAD-, living cells, annexinV+7 AAD-, early apoptotic cells, annexinV+7 AAD+, late apoptotic cells. Fig. 6 shows that TTField in combination with golian Sha Tuozhu mab synergistically inhibited a2780