Compositions and methods comprising protease-activated therapeutic agents

A composition and protease cleavage technology, applied in the field of treating cancer and preparing polypeptides

Pending Publication Date: 2022-05-10
UNIVERSITY OF CHICAGO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, some IL12 clinical trials have been terminated or failed due to its severe toxicity
IL12 has not been approved for clinical use so far

Method used

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  • Compositions and methods comprising protease-activated therapeutic agents
  • Compositions and methods comprising protease-activated therapeutic agents
  • Compositions and methods comprising protease-activated therapeutic agents

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0307] Example 1: Masked cytokines reduce toxicity and increase tumor-specific activation

[0308] Cytokine cancer immunotherapy using interleukin (IL)-12 has shown strong antitumor effects in both mice and humans. However, some IL12 clinical trials have been terminated or failed due to its severe toxicity. IL12 has not been approved for clinical use to date (1).

[0309] Immunotherapy is used to activate the immune response, and as such, side effects often result from the drug's action in healthy organs. One solution to overcome the toxicity problem is to prevent cytokine action in healthy tissue. One solution involves the conversion of cytokines into prodrugs that are inactive in healthy tissue and during the systemic circulation, but are locally activated at disease sites. In antibody form, this concept has been developed as a pro-antibody (2). Fusion of L12 to an anti-IL12 antibody was recently developed to cover the IL12 receptor binding site, however this approach in...

Embodiment 2

[0341] IX. Example 2 - Cytokine Embodiment

[0342] The technique of covering receptor binding sites by fusion of cytokine receptor domains can be applied to other anti-tumor cytokines. This example teaches that the receptor is fused to IL-2 and IFNγ to produce other pro-cytokines, namely pro-IL-2 and pro-IFNγ. In all versions, an MMP and / or thrombin-responsive cleavage site is inserted between the receptor and the cytokine. Exemplary embodiments of cytokines and masking agents are provided below:

[0343] Cytokines masking agent hIL-2 hIL-2Rα hIL-2 hIL-2Rβ hIL-2 hIL-2Rγ mouse IL-2 hIL-2Rα mouse IL-2 hIL-2Rβ mouse IL-2 hIL-2Rγ hIFNγ human IFNγR1 hIFNγ human IFNγR2 mouse IFNγ mouse IFNγR1 mouse IFNγ mouse IFNγR2

Embodiment 3

[0344] Example 3 - Addition of serum protein for prolonged circulation.

[0345] Procytokines can be improved by CBD fusions to prolong tumor residence time, and / or albumin fusions to prolong circulation. Cytokines generally have a short half-life in blood (9). Because procytokine techniques generally rely on proteases in the body (ie, the tumor), it is important to increase the residence time of the injected procytokine in the tumor. The inventors used two approaches to enhance the CND-cytokine platform. The first step is to fuse the collagen-binding domain to the procytokine. As described in Example 1, due to the nature of tumor vasculature, CBD can target and maintain fused proteins in tumors. Thus, the activity of the CBD-procytokine is more specific within the tumor, leading to enhanced efficacy and safety. This is a dual tumor targeting system.

[0346] Another step is to prolong the blood half-life of the procytokine. Since the prolonged blood half-life of the inj...

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Abstract

The present disclosure relates to collagen binding modification engineering of masking therapeutic agents comprising one or more than one tumor-associated protease cleavage site. Upon exposure to a tumor-associated protease in the tumor microenvironment, the polypeptide is cleaved, which exposes the therapeutic agent, reducing off-target side effects and toxicity associated with systemic administration. Thus, aspects of the present disclosure relate to polypeptides comprising a therapeutic agent bound to a masking agent via a linker wherein the linker comprises one or more than one tumor-associated protease cleavage site, and wherein the masking agent blocks the attachment of a therapeutic agent to its therapeutic target, and wherein the polypeptide operably binds to a collagen binding domain or a tumor targeting agent.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to U.S. Provisional Patent Application No. 62 / 878,574, filed July 25, 2019, the contents of which are incorporated herein by reference in their entirety. Background technique [0003] Cytokine cancer immunotherapy using interleukin (IL)-12 has shown strong antitumor effects in both mice and humans. However, some IL12 clinical trials have been terminated or failed due to its severe toxicity. IL12 has not been approved for clinical use so far. Immunotherapy is used to activate the immune response, and as such, side effects often result from the drug's action in healthy organs. There is a need in the art for strategies to reduce treatment toxicity. Contents of the invention [0004] The present disclosure relates to the engineering of collagen-binding modifications of masked therapeutics comprising one or more tumor-associated protease cleavage sites. Upon exposure to tumor-associated...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/20A61P35/00C07K14/54C07K19/00C12N5/10C12N15/09
CPCA61P35/00C07K14/54C07K14/5434C07K14/55C07K14/7155A61K39/39541C07K16/2818C07K2317/76A61K2039/505C07K14/57C07K14/7156C07K14/745C12N9/6429C07K2319/00C07K2319/21C07K2319/50C12N9/6489A61K38/00A61K9/0019A61K45/06A61K47/65A61K47/6425C07K2319/33A61K2300/00A61K47/6851A61K47/6845A61K39/3955
Inventor 杰弗里·哈贝尔石原纯胡安·门多萨阿斯兰·曼苏罗夫
Owner UNIVERSITY OF CHICAGO
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