JP-2026076268-A - A method for minimizing adverse effects mediated by external influences on cells, tissues, organ systems, and living organisms by utilizing the bioadhesion and steric interactions of copolymers having at least two sites.

Abstract

[Problem] To provide a method for minimizing adverse effects mediated by external influences on cells, tissues, organ systems, and living organisms. [Solution] A method is provided for treating with an effective amount of a graft or block copolymer having cationic, hydrophobic, or anionic sites and hydrophilic inactivation sites. The copolymer is PLL-g-PEG. The copolymer exhibits bioadhesion through electrostatic and hydrophobic interactions, as well as inactivation by the hydrophilic sites. The copolymer is useful for reducing the viral infection rate of target cells and reducing host morbidity. The copolymer is useful for reducing toxicity associated with ADCs, including corneal epithelial toxicity. Formulations of the copolymer are safe and well tolerable. Usefulness and benefits can be obtained by treating epithelial cells and surfaces, including precursor or stem cell corneal epithelial cells, with the copolymer. [Selection Diagram] None

Inventors

• デイヴィッド エム． クラインマン

Assignees

• カーム ウォーター セラピューティクス エル・エル・シー

Dates

Publication Date

20260511

Application Date

20260123

Priority Date

20200507

Claims (20)

1. A method for reducing viral infectivity by treating tissue involved in transfection with an effective amount of a graft or block copolymer having cationic, hydrophobic, or anionic sites and hydrophilic inactivation sites.
2. The method according to claim 1, wherein the copolymer is PLL-g-PEG.
3. The method according to claim 1, wherein the graft copolymer of the formulation comprises a cationic backbone and water-soluble and nonionic side chains.
4. The method according to claim 1, wherein the block copolymer of the formulation comprises at least one cationic block and at least one water-soluble and nonionic block.
5. The method according to claim 1, wherein the block copolymer of the formulation comprises at least one hydrophobic block and at least one block that is water-soluble and anionic, cationic, or nonionic.
6. The method according to any one of claims 1 to 5, wherein the biological surface to which the copolymer formulation is administered is a mucous membrane selected from the ocular mucosa, oral mucosa, nasal mucosa, and respiratory tract mucosa, respiratory tract epithelium, urinary tract mucosa, and gastrointestinal mucosa of the subject.
7. The method according to claim 6, wherein the biological surface to which the copolymer formulation is administered is the surface of the eye.
8. The method according to any one of claims 1 to 5, wherein the viral infection is selected from coronavirus, influenza virus, Ebola virus, and novel viruses transmitted by mucosal exposure.
9. The method according to claim 8, wherein the virus is SARS-CoV-2.
10. The method according to any one of claims 1 to 9, wherein the graft copolymer or block copolymer of the formulation constitutes 0.001 to 40% of the formulation.
11. The method according to any one of claims 1 to 9, wherein the graft copolymer or block copolymer of the formulation constitutes 0.1 to 10% of the formulation.
12. The method according to claim 8, wherein the inactivation effect is based on the interference of the SARS-CoV-2 spike protein and the ACE2 receptor on cells at risk.
13. The therapeutic effect is general steric inhibition, as described in claim 1.
14. A method for reducing adverse events associated with the use of antibody-drug conjugates that damage non-neogeneic cells (which exhibit adverse effects) by applying an effective amount of a copolymer having electrostatic and steric mediating properties to cells and tissues (that are adversely affected by the use of antibody-drug conjugates).
15. The method according to claim 14, wherein the copolymer is selected from cationic graft copolymers, cationic block copolymers, hydrophobic graft copolymers, hydrophobic block copolymers, anionic graft copolymers, and anionic block copolymers.
16. The method according to claim 14 or 15, wherein the copolymer is formulated by one or more approaches from among powder, solution, suspension, topical agent, intravenous agent, oral agent, mouthwash, nasal spray, and eye drop.
17. The method according to claim 14 or 15, wherein the proportion of the copolymer solution is at least 0.01% by weight.
18. The method according to claim 14 or 15, wherein the proportion of the copolymer solution is at most 40% by weight in the case of a solution and a suspension.
19. The method according to claim 14, wherein the copolymer is PLL-g-PEG.
20. The method according to claim 14, wherein the copolymer is selected from the list of combinations described in the above-mentioned application.

Description

Priority: This application claims the benefit of U.S. Provisional Application No. 63/021,277, filed on 7 May 2020, which is incorporated herein by reference in its entirety. Field of Invention The present invention provides a method to address significant problems currently faced in the biomedical field by improving the health of cells, tissues, organs and mammals using bioadhesive and inactivating copolymers (including charged or hydrophobic sites and inactivating hydrophilic sites). Specifically, the field of the invention relates to the prevention, attenuation, reduction or treatment of viral infections. More specifically, the field of the invention relates to the prevention, attenuation, reduction or treatment of toxicity associated with drugs associated with antibody-drug conjugates (ADCs) and their toxic payloads. "ADC" is frequently used herein to represent antibody-drug conjugate therapeutics. An ADC is a complex molecule consisting of an antibody conjugated to a biologically active cytotoxic (anti-cancer) payload or drug. Antibody-drug conjugates can be a type of bioconjugate and immunoconjugate. "ADC" may mean the host of various antibody-drug conjugates herein. ADCs combine the targeting ability inherent in monoclonal antibodies with the cancer-fighting ability of cytotoxic drugs. ADCs are often designed to distinguish between healthy cells and tissues and diseased cells and tissues. The viral infection of particular interest here is that of SARS-CoV-2. However, a significant development is that this effect is also effective against novel viruses, as steric and electrostatic interactions can suppress the infectivity of novel viruses to cells, tissues, or organisms where host immunity is not yet developed or where targeted antibodies or antiviral therapies are not yet available. In other words, this effect is broad-spectrum, effective, and non-specific. Novel viruses are well-suited to treatment using this approach. Methods for mitigating the toxicity of ADCs are particularly related to the off-target entry of ADCs into non-neogeneic cells and adverse events associated with the inhibition of cellular processes mediated by the ADC payload. Neogeneic cells are cancer cells. ADCs are used to treat cancer or neoplastic diseases of one or more organ systems or cell types, including but not limited to renal cell carcinoma, leukemia, lymphoma, myeloma, lung cancer, prostate cancer, uterine or cervical cancer, breast cancer, bladder cancer, colon cancer, esophageal cancer, liver cancer, Hodgkin's disease, ovarian cancer, pancreatic cancer, rectal cancer, skin cancer, small intestine cancer, solid tumors, gastric cancer, leukocyte cancer, urethral cancer, and mesenteric lymphadenitis. Any or all of the cancers named herein and/or not named herein may be combined with claims relating to specific inventions of ADCs targeting such cancer cells or tissues. Specifically, macropinocytosis-mediated toxicity is inhibited, reduced, and limited by steric and electrostatic interference acting at the molecular-cell-tissue (integrated or isolated) level, where the surface of a cell or tissue interacts with its local microenvironment. Cells include, but are not limited to, marginal stem cells, transient amplified cells, transient amplified cell daughter cells, basal epithelial cells, alar cells, and corneal epithelial cells and differentiated corneal epithelial cells. The most useful (but not the only useful) primary underlying polymer structure in both settings is the cationic graft copolymer. This basic structure comprises a cationic backbone and grafted hydrophilic side chains. A representative example of such polymers is poly(L)lysine grafted (poly)ethylene glycol. Other molecular structures also achieve the interactions necessary to confer benefits. Other polymers may utilize charge, hydrophobic, and deactivating sites to achieve these effects, and these polymers are discussed herein. The therapeutic method is carried out by applying the aforementioned polymers (whether in a dissolved state or not) to cells, tissues, organs, living organisms, or mammals in amounts and for durations effective in achieving the intended beneficial effect. Therefore, there is a need to reduce the severity and risk associated with novel viral diseases that spread to human populations and affect human health. Furthermore, there is a need to reduce the negative effects associated with antibody-drug conjugates, particularly corneal epithelial toxicity. Background of the Invention Cationic graft copolymers have been demonstrated to be useful in in vitro coating of non-biological surfaces, coating of medical devices, and treatment of dry eye. An example of an effective cationic graft copolymer is poly(L-lysine) grafted poly(ethylene glycol) (PLL-g-PEG). PLL-g-PEG is a water-soluble copolymer consisting of a poly(L-lysine) backbone and poly(ethylene glycol) side chains (Sawhney et al. Biomaterials 1992 13:863-870). The PLL chain has multiple