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CN-121975901-A - Combined drug development method based on 3D human cancer model

CN121975901ACN 121975901 ACN121975901 ACN 121975901ACN-121975901-A

Abstract

The present application relates to a method for characterizing a composition comprising two or more active pharmaceutical compounds, comprising the steps of a) Composition Selection Screening (CSS) in which candidate compositions comprising two or more active pharmaceutical compounds are tested with 3D micro-tissues of one or more cell line origin, and b) Composition Verification Screening (CVS) in which candidate compositions of step b) are tested with 3D micro-tissues of primary patient sample origin.

Inventors

  • Jens Michael Colm
  • PETER STEINER

Assignees

  • 普瑞康铂医疗公司

Dates

Publication Date
20260505
Application Date
20191120
Priority Date
20181120

Claims (20)

  1. 1. A method of characterizing the physiological effects of a composition comprising two or more active pharmaceutical compounds, the method comprising the steps of: b) Composition Selection Screening (CSS) in which 3D micro-tissues derived from one or more cell lines are exposed to a composition comprising two or more active pharmaceutical compounds, and/or C) Composition Verification Screening (CVS) in which primary patient sample-derived 3D micro-tissues are exposed to the composition of step b), To characterize the physiological effect of the composition on 3D micro-tissue.
  2. 2. A method according to claim 1, wherein at least one parameter indicative of the characterized physiological effect is generated or determined from the method.
  3. 3. The method of claim 1 or 2, further comprising A) A Range Finding Step (RFS) in which a plurality of 3D micro-tissues derived from one or more cell lines are exposed to each compound present in a composition at a different concentration to determine a suitable concentration range of the compound.
  4. 4. The method according to any one of the preceding claims, further comprising the step of obtaining a molecular profile of at least one of the one or more cell line-derived 3D micro-tissues, and/or the primary patient sample-derived 3D micro-tissues.
  5. 5. The method according to any one of the preceding claims, wherein the step of obtaining a molecular profile is used to detect genomic abnormalities, and/or mRNA or protein expression levels.
  6. 6. Method according to any of the preceding claims, in which method parameters representing the characterized physiological effect are determined over time in at least one of steps a), b) and/or c).
  7. 7. A method according to any one of the preceding claims, in which the parameter indicative of the physiological effect characterized is the size of the 3D micro-tissue.
  8. 8. A method according to any one of the preceding claims, in which method the dimensions are actual dimensions, relative dimensions, and/or relative dimensional changes over time determined in at least one of steps a), b) and/or c).
  9. 9. The method according to claim 7 or 8, in which method the sizing of the 3D micro-tissue refers to at least one parameter selected from the group consisting of diameter, circumference, volume and/or optical cross-sectional area.
  10. 10. The method according to any one of claims 7-9, in which method the dimensions are determined in at least one of steps a), b) and/or c) over a period of more than 1 day and less than 20 days.
  11. 11. The method according to any one of the preceding claims, wherein the 3D micro-tissue is exposed to the active pharmaceutical compound of step a) or the composition of steps b) and c) containing two or more active pharmaceutical compounds only once by administering a specified single dose.
  12. 12. The method according to any one of the preceding claims, wherein the 3D micro-tissue is exposed to the active pharmaceutical compound of step a) or the composition of steps b) and c) containing two or more active pharmaceutical compounds more than twice by each administration of a specified single dose.
  13. 13. The method of any one of the above claims, wherein a composition comprising two or more active pharmaceutical compounds is removed after the microtissue is exposed for a specified period of time.
  14. 14. The method according to any one of the preceding claims, further comprising a step of toxicity testing the composition, wherein, (I) Exposing the micro-tissue representing connective tissue to the composition of step b), and/or (Ii) Exposing the tissue-specific micro-tissue to the composition of step c), To characterize the physiological effect of the composition on the micro-tissue.
  15. 15. The method according to any one of the preceding claims, wherein at least one 3D micro-tissue is produced in a hanging drop culture system or a low adhesion plate culture system.
  16. 16. The method according to any of the preceding claims, wherein the molecular profile of at least one 3D micro-tissue is correlated with at least one parameter characterizing physiological effects obtained in a Composition Selection Screen (CSS) or a Composition Verification Screen (CVS) of the 3D micro-tissue.
  17. 17. The method of claim 16, further comprising the step of creating or expanding a database with a data set comprising at least the following entries: a) At least one molecular map of at least one 3D micro-tissue, and B) At least one parameter characterizing physiological effects obtained in a Composition Selection Screen (CSS) or a Composition Verification Screen (CVS) of the 3D micro-tissue.
  18. 18. A method for screening a plurality of compositions containing two or more active pharmaceutical compounds, preferably from one or more libraries, the method comprising: (i) The administration of two or more methods according to any one of the preceding claims, using different compositions containing two or more active pharmaceutical compounds in each method, and/or (Ii) A plurality of sets of steps b), c) and optionally a).
  19. 19. The method of claim 18, wherein the compositions comprising two or more active pharmaceutical compounds differ from each other in that A) Composition of active pharmaceutical compounds, or B) The dosage or concentration of the active pharmaceutical compound in the composition.
  20. 20. The method according to any of the preceding claims, further comprising at least one step selected from the group consisting of: a) Synthesizing an active pharmaceutical compound contained in the composition, B) Combining a composition comprising two or more active pharmaceutical compounds, and/or C) A library of active pharmaceutical compounds and/or compositions containing two or more active pharmaceutical compounds is created that are comprised in the above-described compositions.

Description

Combined drug development method based on 3D human cancer model The application is a division of PCT Chinese national stage application 201980075877.8 submitted on 11 months and 20 days in 2019. Technical Field The present application relates to a method for characterizing a composition comprising two or more active pharmaceutical compounds, comprising the steps of b) Composition Selection Screening (CSS) in which candidate compositions comprising two or more active pharmaceutical compounds are tested with 3D micro-tissues of one or more cell line origin, and c) Composition Verification Screening (CVS) in which candidate compositions of step b) are tested with 3D micro-tissues of primary patient sample origin (FIG. 1). Background The present application relates to screening of therapeutic drug combinations. In general, the utility of therapeutic agents is screened in conventional screening systems, wherein the agents in a library are tested in a suitable cell-based assay. Generally, the survival rate of cells and/or the toxicity of drug candidates is investigated. Such methods can typically be performed at high throughput, but with a higher risk of hopefully falling empty in subsequent clinical tests for drugs identified as promising in the method. Furthermore, it has been found that in the field of specific indications, pharmaceutical compositions are increasingly used, for example to avoid the occurrence of drug resistance, or to explore synergistic effects. To date, few systematic approaches have been disclosed for early screening of potential drug combinations. Drugs are typically combined by a physician based on their experience and tested in a patient. However, there is a lack of systematic methods to truly study the combined effects of these pharmaceutical compositions. This means that there may be a large number of promising pharmaceutical compositions, but there is no opportunity for the patient to use due to the lack of systematic research methodology. At the same time, there is a need to improve the predictability of early experiments in future in vivo environments to reduce the risk of failure of drug combinations that have been demonstrated to perform well in preclinical experiments. In addition, there is a need for faster, more efficient determination of new drug combinations with sustainable therapeutic efficacy. WO 2013/050962A1 relates to a drug-containing tumor microenvironment platform for culturing tumor tissue, a method of predicting tumor response to a drug, and a method of screening or developing an anticancer drug. WO 2017/081260A1 relates to the use of three-dimensional spheroids in screening potential therapeutic drugs, wherein the screening is a high throughput screening of a pool of potential therapeutic drugs. US 2016/040132A1 relates to bioprinted three-dimensional pancreatic tumor tissue, and methods of identifying therapeutic agents for such tumors. The above documents do not mention the necessity of studying the combined effect of two or more drugs, and the advantages of the newly discovered drug combinations. These and other objects are achieved by the method and means of the independent claims. The dependent claims relate to preferred embodiments. It should be understood that numerical ranges defined by numerical values are to be construed as inclusive of the defined end points. Disclosure of Invention Before describing the present application in detail, it is to be understood that this application is not limited to particular components of the apparatus or to the method steps of operation as such apparatus and methods may vary. Also, it is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. It is noted that, as used in the specification and the appended claims, the singular forms "a," "an," and "the" include the singular and/or plural forms unless the context clearly dictates otherwise. Furthermore, it is to be understood that where a range of parameters is defined by numerical values, that range is equivalent to inclusive of the recited end points. Furthermore, it should be noted that the documents or content incorporated by reference herein are primarily provided for the purpose of disclosure, thereby avoiding excessive text. According to one embodiment of the present application, a method of characterizing the physiological effects of a composition comprising two or more active pharmaceutical compounds is provided. The method comprises the following steps: b) Composition Selection Screening (CSS) in which 3D micro-tissues derived from one or more cell lines are exposed to a composition comprising two or more active pharmaceutical compounds, and/or C) Composition Verification Screening (CVS) in which primary patient sample-derived 3D micro-tissues are exposed to the composition of step b), To characterize the physiological effect of the composition on 3D micro-tissue. It is im