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Chimeric activators: quantitatively designed protein therapeutics and uses thereof

a technology of chimeric activators and protein therapeutics, applied in the field of chimeric proteins, fusion proteins, and therapeutic proteins, can solve the problems that erythropoietin can also have serious side effects, and achieve the effect of reducing cell activation properties and avoiding or reducing unwanted side effects

Pending Publication Date: 2017-10-26
PRESIDENT & FELLOWS OF HARVARD COLLEGE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The invention relates to methods and compositions for targeting the activity of naturally-occurring proteins to specific cells or tissues, while avoiding or reducing unwanted side effects on non-target cells. This is achieved by using chimeric proteins that include a cell-activating element and a targeting element joined by a linker. The targeting element binds to a specific binding site on a target cell, while the activity element binds to a different binding site on the same cell. The linker length is optimized to maximize the binding efficiency of the activity element to the second binding site when the targeting element is bound to the first binding site. This approach can be used to target cells involved in cancer or other diseases, while avoiding or reducing toxicity. The invention also provides methods for manufacturing and using the chimeric activator.

Problems solved by technology

Erythropoietin can also have serious side effects when treating anemia associated with cancer, since erythropoietin can stimulate the growth and survival of certain cancer cells.

Method used

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  • Chimeric activators: quantitatively designed protein therapeutics and uses thereof
  • Chimeric activators: quantitatively designed protein therapeutics and uses thereof
  • Chimeric activators: quantitatively designed protein therapeutics and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

GF Chimeric Activator

[0121]In some embodiments, a Chimeric Activator protein was constructed with the following protein components: a mutated version of interferon alpha (IFNα) as the Activating Element, a linker, and epidermal growth factor (EGF) as the targeting element. An embodiment of this chimeric protein is illustrated in FIG. 3. In FIG. 3, the IFNα activity element is shown in region (1), the (Gly4Ser)7 linker is shown in region (2), and the EGF targeting element is shown in region (3). In FIG. 3, the Chimeric Activator is bound to both IFNαR2 (shown as region (4)) and an active EGFR dimer (shown as region (5)). The figure shows only the extracellular domains of the receptors. The membrane-spanning domains would be at the bottom of the figure.

[0122]These elements were chosen based on the following considerations. The published structure of EGF receptor with a ligand (Garrett et al. (2002) Cell 110: 763-773) and a model of the IFNα structure (Quadt-Akabayov et al. (2006) Prot...

example 2

Activator in an Animal Tumor Model

[0135]Chimeric Activators of Example 1 can be tested / screened for activity in animal tumor models. Pharmaceutical Product Development, Inc. (New York, N.Y.) can be used as a contract testing service to perform these tests. This type of experiment is standard in the development of anti-cancer drugs, and involves injection of human tumor cells into mice that have immune-suppressing mutations so that the tumor cells will not be rejected. In one form of the experiment, tumor cells are injected subcutaneously and then grow into a lump that can be measured with calipers. Once a tumor has reached a measurable size, treatment is started and the extent of tumor growth inhibition or shrinkage can be charted with time.

[0136]Using IFNα(R149A)-EGF as the test molecule, experiments can be performed in parallel sets of animals used paired tumor cell lines, one of which expresses the receptor for the targeting element, and one of which does not. The Daudi and Daudi...

example 3

rosis Factor α (TNFα) as an Activity Element

[0146]To demonstrate the breadth of the Chimeric Activator concept, each element (activity element, a linker, and a targeting element) of the constructs of Example 1 can be replaced with an alternative component that is structurally different and / or has a different biological function. This is illustrated in this example and those that follow. These experiments may provide a molecule for testing in animals.

[0147]To demonstrate that IFNα can be replaced by other activators of signal transduction, a series of proteins with wild-type and mutant versions of Tumor Necrosis Factor (TNFα) can be constructed. Specifically, the following series of mutations defined by Zhang et al. ((1992) J Biol Chem. 267: 24069-24075) can be used:

MutationRelative activityWild-type100%N39Y30%S147Y7%Y87H0.6%

[0148]TNF is a trimer with a completely different structure from IFNα. The structure of the TNF / TNF receptor complex has been solved. The N-terminus and C-termin...

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Abstract

Aspects of the invention provide methods for harnessing the potential of proteins that occur naturally (e.g., in humans) and that have serious but finite toxicity. Aspects of the invention relate to a quantitative systems-biological and structural approach to design a class of chimeric proteins that avoid the toxicity of protein drugs while retaining their desired activities. In particular, chimeric proteins containing a variant form of a natural protein fused to a targeting moiety may be administered to a subject to target a signal (e.g., induction of apoptosis) to particular cells without having a generalized toxic effect in the subject.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation of co-pending U.S. application Ser. No. 12 / 594,747 filed Apr. 16, 2010, which is a 35 U.S.C. §371 National Phase Entry Application of International Application No. PCT / US08 / 04435 filed Apr. 5, 2008, which designates the U.S. and which claims the benefit under 35 U.S.C. §119(e) from U.S. provisional applications Ser. No. 60 / 910,390 filed Apr. 5, 2007, Ser. No. 61 / 005,775 filed Dec. 7, 2007 and Ser. No. 61 / 065,937 filed Feb. 15, 2008, the entire contents of which are herein incorporated by reference.SEQUENCE LISTING[0002]The instant application contains a Sequence Listing which has been submitted in ASCII format via EFS-Web and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Jun. 19, 2017, is named Sequence-Listing-12594747.txt and is 56,625 bytes in size.FIELD OF THE INVENTION[0003]The invention relates to chimeric proteins, fusion proteins, and therapeutic proteins.BACKGR...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07K16/28C07K14/485C07K14/56C07K14/575C07K16/30C07K14/525A61K38/00
CPCC07K2317/76C07K2317/34C07K2319/74C07K2319/33C07K2319/30C07K2317/622C07K16/3007C07K16/2896C07K16/2863C07K14/5759C07K14/56C07K14/525C07K14/485A61K47/48576A61K47/48561A61K47/48423A61K47/48276A61K47/48269A61K38/00A61K47/642A61K47/6425A61K47/6813A61K47/6849A61K47/6853A61P11/06A61P3/04A61P31/18A61P35/00A61P7/06
Inventor SILVER, PAMELA A.CIRONI, PABLOMIGUEZ, DAVID G.
Owner PRESIDENT & FELLOWS OF HARVARD COLLEGE
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