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Protocol for minimizing toxicity of combination dosages and imaging agent for verification

Pending Publication Date: 2020-11-19
PROLYNX LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The invention aims to minimize the negative effects of chemotherapy on healthy cells while treating tumors effectively. This can be achieved by administering drugs in a specific way to avoid direct contact with normal tissue. One approach involves using nanoparticles or macromolecules that can carry both drugs and be targeted to tumors using enhanced permeability and retention (EPR). These particles can be designed to release the drugs in tumors and be cleared from normal tissue, resulting in higher concentrations of drugs in tumor cells while minimizing toxic effects on healthy tissues. The use of a multi-armed PEG can improve the efficiency of this approach.

Problems solved by technology

Chemotherapeutic agents that are used to treat solid tumors are toxic to normal tissue as well.
Levels of such agents administered are limited by their maximum tolerated dose.
When combinations of such agents are used, the toxicity of both agents is experienced by normal tissue which further limits effective dosage levels.
This problem has been addressed by designing protocols that avoid simultaneous administration of more than one agent essentially on a trial-and-error basis which does not lead to optimal results.
The larger pores in the tumor neovasculature result in leakiness that allows macromolecules and nanoparticles to penetrate and extravasate into the tumor and this combined with poor lymphatic drainage results in the EPR effect which results in accumulation of macromolecules, conjugates or nanoparticles that is generally related to size and flexibility of the nanoparticle or macromolecule and exposure (i.e., t1 / 2).

Method used

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  • Protocol for minimizing toxicity of combination dosages and imaging agent for verification
  • Protocol for minimizing toxicity of combination dosages and imaging agent for verification
  • Protocol for minimizing toxicity of combination dosages and imaging agent for verification

Examples

Experimental program
Comparison scheme
Effect test

example 1

Administration of Conjugated SN-38

[0099]SN-38 is the topoisomerase I inhibitor that is the active drug released from the prodrug, irinotecan. Conjugates of SN-38 are described in WO 2015 / 051307. Two different conjugates of SN-38 were prepared: PLX038 and PLX038A. These conjugates couple the drug releasably to a four-armed PEG of 40 kD through a linker that effects release by β-elimination. The structure of PLX038 and PLX038A is shown below wherein “Mod” is CN in PLX038, and methyl sulfonyl in PLX038A.

[0100]Six rats bearing HT29 tumor xenografts were injected with 200 mg / kg of PLX038 and the concentration in plasma and tumor of the conjugate and released drug as well as its glucuronide (SN-38G) were followed by HPLC with fluorescence monitoring As shown in FIG. 1, the half-life of PLX038 in the systemic circulation is about 50 hours. The conjugate and the free drug as well as SN-38G show similar half-lives.

[0101]As shown in FIG. 2, the efficacy of a non-toxic dose of 20 nmol / kg of SN...

example 2

Suggested Human Protocol

[0103]A dosing schedule in humans for a combination of PLX038 and a second drug (e.g., a PARP inhibitor) administered systemically is proposed wherein PLX038 is administered on day 1 whereby the conjugate accumulates in the tumor and releases the free drug. The conjugate and the free drug are concomitantly cleared from the system. After two half-lives of systemic clearance or 10 days, systemic PLX038 is reduced to 25% of its original concentration, which lies below its minimal effective and toxic levels. At this time the second drug, which is synergistic with SN-38 is administered orally for 20 days.

[0104]As shown in FIG. 4, the EPR effect concentrates PLX038 in the tumor (dotted line), while the systemic PLX038 (solid line) is sufficiently low that any toxic effect is only to a second drug, which is administered as shown at 10 days. At that time, the concentration of the conjugate in the tumor is still above the minimum effective level but below the toxic le...

example 3

Design of a Mouse Model

[0105]Because most xenograft tumor models use mice as hosts, it is desirable to adapt the protocols of the present invention to testing in mice. Adaptation is needed because the half-life of the PLX038 conjugate in the mouse is only about 24 hours, whereas in the rat it is about 48 hours and in humans about 6 hours. Because the more rapid elimination of PLX038 in mice occurs before substantial amounts of the SN-38 are released, a different conjugate of SN-38, PLX038A that has a higher cleavage rate, is used in murine experiments.

[0106]Linker cleavage is species independent. While 32% of PLX038 is converted to SN-38 over one half-life of the conjugate in humans, only 12% is converted in the rat and 6% in the mouse. For PLX038A, the cleavage half-life is 70 hours and 26% conversion to SN-38 over one half-life of the conjugate in the mouse occurs. This conjugate also can be administered intraperitoneally (IP) in mice with 100% bioavailability.

[0107]However, in mi...

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Abstract

Advantage is taken of the enhanced permeability and retention effect (EPR effect) to shield normal tissue from exposure to combinations of chemotherapeutic agents. Imaging agents that exhibit the enhanced permeability and retention (EPR) effect in solid tumors are useful in mimicking the behavior of chemotherapeutic or other drugs for treatment of said tumor conjugated to carriers of similar size and shape to the carriers of said imaging agents.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims priority from U.S. provisional application 62 / 617,095 filed 12 Jan. 2018, U.S. provisional application 62 / 674,483 filed 21 May 2018, U.S. provisional application 62 / 711,421 filed 27 Jul. 2018, U.S. provisional application 62 / 716,788 filed 9 Aug. 2018, U.S. provisional application 62 / 716,796 filed 9 Aug. 2018, U.S. provisional application 62 / 700,147 filed 18 Jul. 2018, and U.S. provisional application 62 / 711,423 filed 27 Jul. 2018, the disclosures of which are herein incorporated by reference in their entirety.TECHNICAL FIELD[0002]The invention is in the field of combination treatments of solid tumors and of diagnostic methods that assess pharmacokinetics of administered entities, specifically with respect to the enhanced permeability and retention (EPR) effect exhibited when entities of nanometer dimensions are administered to subjects with solid tumors. More specifically, the invention relates to taking advantage ...

Claims

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Application Information

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IPC IPC(8): A61K51/06A61K47/60A61K9/51
CPCA61K45/06B82Y5/00A61K51/065A61K47/60A61K9/51A61K9/0019A61K31/4995A61K33/243A61K31/555A61K31/513A61K31/475A61K31/495A61K31/5025A61K2300/00A61P35/00A61K47/6935A61K31/4745
Inventor HEARN, BRIANSANTI, DANIEL V.FONTAINE, SHAUNASHLEY, GARY W.
Owner PROLYNX LLC
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