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Combination therapy

A technology for binding molecules and binding domains, which can be used in drug combinations, antibody medical components, chemical instruments and methods, etc., and can solve problems such as reducing a variety of cytokines

Inactive Publication Date: 2019-02-05
MACROGENICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

More specifically, it has been found that the interaction between the PD-1 receptor and the B7-H1 ligand at low concentrations results in the transmission of an inhibitory signal that strongly inhibits the antigen-specific CD8 + Proliferation of T cells; at higher concentrations, the interaction with PD-1 did not inhibit T cell proliferation, but significantly reduced the production of various cytokines (Sharpe, A.H. et al., (2002) "The B7-CD28 Superfamily, "Nature Rev. Immunol. 2:116-126)

Method used

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Embodiment approach

[0277] As stated above, the present invention relates to combination therapy for the treatment of cancer comprising the administration of:

[0278] (1) A molecule capable of binding PD-1 or a natural ligand of PD-1; and

[0279] (2) Molecules capable of mediating redirected killing of target cells (eg, diabodies, BiTe, bispecific antibodies, etc.).

[0280] The invention also relates to pharmaceutical compositions comprising such molecule(s).

[0281] As used herein, the term "administration" refers to providing such molecules in relative doses and in temporal proximity to provide the recipient with binding to PD-1 or a natural ligand of PD-1 and to target cells ( For example, both redirected killing of cancer cells or of pathogen-infected cells).

[0282] With respect to molecules capable of binding PD-1 or natural ligands of PD-1, the present invention particularly relates to wherein such molecules possess an epitope that immunospecifically binds PD-1 to inhibit (i.e., blo...

Embodiment 1

[0973] Combination Therapy Study: LOX-IMVI Tumor Model

[0974] To illustrate the principles of the present invention, combination therapy studies were performed using a reconstituted tumor model in which LOX-IMVI human metastatic melanoma cancer cells were injected subcutaneously into MHCI reconstituted with human PBMC - / - in mice. Mice were then administered vehicle or the following treatments:

[0975] (1) Humanized anti-human PD-1 antibody: hPD-1 mAb7(1.2) IgG4(P), this type of antibody is a molecule capable of binding PD-1; and / or

[0976] (2) CD3 x B7-H3 bispecific diabody DART-A, this type of diabody is a molecule that can bind to a cell surface molecule (ie, CD3) of effector cells and can bind to a cancer antigen (ie, B7-H3), This can mediate redirected killing of B7-H3-expressing cancer cells.

[0977] The amino acid sequences of such administered molecules are described above. Table 11 shows the parameters of the study. Each group consisted of 6 female mice. Fo...

Embodiment 2

[0981] Combination Therapy Study: Detroit562 Tumor Model

[0982] To further illustrate the principles of the present invention, a combination therapy study was performed using a reconstituted tumor model in which Detroit562 human metastatic pharyngeal carcinoma cells were subcutaneously injected into MHCI reconstituted with human PBMC - / - in mice. Mice were then administered vehicle control, 1 mg / kg hPD-1 mAb7(1.2) IgG4(P), 0.5 mg / kg DART-A or 1 mg / kg hPD-1 mAb7(1.2) IgG4(P) and 0.5 mg / kg hPD-1 mAb7(1.2) IgG4(P) kg DART-A both. Table 12 shows the parameters of the study. Each group consisted of 8 male mice. For all groups, mice received 5 x 10 6 Detroit562 cancer cell (ID) and 10 6 Human PBMC (IP; administered on study day 0). Treatment (molecule(s) or vehicle administered starting on study day 7) was provided weekly for four weeks (Q7Dx4) or every 14 days for up to two doses (Q14Dx2); via Doses were administered intravenously.

[0983]

[0984] Measure tumor volum...

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Abstract

The present invention is directed to a combination therapy for the treatment of cancer and pathogen-associated diseases, that comprises the administration of: (I) a molecule (e.g., a diabody, an scFv,an antibody, a TandAb, etc.) capable of binding PD-I or a natural ligand of PD-I, and (2) a molecule (e.g., a diabody, a BiTe, a bispecific antibody, a CAR, etc.) capable of mediating the redirectedkilling of a target cell (e.g., a cancer cell or a pathogeninfected cell, etc.) expressing a Disease Antigen. The invention particularly concerns the embodiment in which the molecule capable of mediating the redirected killing of the target cell is a bispecific binding molecule that comprises a first epitope-binding site capable of immunospecifically binding an epitope of a cell surface molecule of an effector cell and a second epitope-binding site that is capable of immunospecifically binding an epitope of such target cells.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to U.S. Patent Application Serial Nos. 62 / 346,854 (filed June 7, 2016; pending) and 62 / 432,299 (filed December 9, 2016; pending), each This application is hereby incorporated by reference in its entirety. [0003] Reference to Sequence Listing [0004] Pursuant to 37 C.F.R. 1.821 and the following clauses, this application includes one or more Sequence Listings, which are disclosed on a computer-readable medium (file name: 1301_0142PCT_ST25.txt, created May 31, 2017, and is 225,335 bytes in size) , which is incorporated herein by reference in its entirety. technical field [0005] The present invention relates to a combined therapy for the treatment of cancer and pathogen-related diseases, which includes the administration of: (1) molecules capable of binding to PD-1 or natural ligands of PD-1 (for example, diabodies, ScFv, antibodies, TandAb, etc.) , and (2) molecules (eg, diabodies, ...

Claims

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Application Information

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IPC IPC(8): A61K39/395C07K16/28A61P35/00A61P31/00
CPCA61P31/00A61P35/00C07K16/2809C07K16/2818C07K16/2827A61K2039/505A61K2039/507A61K2039/545C07K2317/31C07K2317/626C07K16/2866C07K16/2803A61K2039/585C07K16/2806C07K16/2815C07K16/283C07K16/2878C07K16/30C07K2317/622
Inventor 埃兹奥·泊韦尼S·凯尼格莱斯利·S·约翰逊保罗·A·摩尔拉尔夫·F·奥尔德森J·M·威金顿
Owner MACROGENICS INC