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Anti-pdl1, il-15 and tgf-beta receptor combination molecules

A molecule and receptor technology, applied in the field of multimer fusion molecules, which can solve problems such as unobserved

Pending Publication Date: 2020-10-30
阿尔托生物科学有限责任公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

13,16 Furthermore, although clinical benefits have been observed with avelumab in a range of human tumors, no adverse events exceeding those seen with other anti-PD1 / PD-L1 MAbs have been observed

Method used

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  • Anti-pdl1, il-15 and tgf-beta receptor combination molecules
  • Anti-pdl1, il-15 and tgf-beta receptor combination molecules
  • Anti-pdl1, il-15 and tgf-beta receptor combination molecules

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Embodiment 1

[0294] Example 1: Generation and characterization of fusion protein complexes comprising IL-15, anti-PDL1, and TGFβRII domains

[0295] Important therapeutic approaches for treating cancer or infectious disease rely on boosting immune cell activity against diseased cells. Such strategies include ex vivo stimulation of immune cells followed by adoptive transfer and / or direct increase of immune cell levels or activity in the patient. The immune cells involved in these methods can be immune cells of the innate (ie, NK cells) or adaptive (ie, T cells) immune system.

[0296] One approach for enhancing immune activity is to provide immune cells with immunostimulatory cytokines. Such cytokines are known in the art and may be used alone or in combination with other cytokines or agents. As described in detail below, we generated fusion protein complexes comprising: fused to an antibody (Ab) or antibody-binding antibody (Ab) that can bind to the immune checkpoint protein programmed d...

Embodiment 2

[0674] Example 2. Biological activity of fusion protein complexes comprising IL-15, anti-PDL1, and TGFβRII domains. Various methods were used to characterize the biological activity of the complexes of the invention ( Figure 9 )

[0675] IL-15 immunostimulatory activity: Based on IL-15-dependent proliferation of 32Dβ cells (a mouse hematopoietic cell line), assessment of IL- 15 Immunostimulatory activity. Increasing levels of αPDL1 / TxM / TGFβRII, TGFβRII / αPDL1 / TXM, or αPDL1 / TGFβRII / TXM were added to 32Dβ cells in 200 μL RPMI:10% FBS medium (10 4 cells / well) and incubated these cells at 37°C for 3 days. Then PrestoBlue Cell Viability Reagent (20 μL / well) was added. After 4 hours, absorbance was measured at 570 nm (with a reference wavelength of 600 nm for normalization) to determine cell proliferation by metabolically active cells, based on the reduction of PrestoBlue, a resazurin-based solution. The half-maximal effective concentration (ECC) for IL-15 bioactivity against α...

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Abstract

The invention features multi- specific protein complexes with one domain comprising IL-15 or a functional variant, a cytokine receptor or cytokine ligand, and a binding domain specific to a disease antigen, immune checkpoint or signaling molecule.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of priority under 35 U.S.C. §119(e) to U.S. Provisional Application No. 62 / 648,373, filed March 26, 2018, and U.S. Provisional Application No. 62 / 734,994, filed September 21, 2018. The entire contents of these applications are hereby incorporated by reference in their entirety. technical field [0003] The present invention relates generally to the field of multimeric fusion molecules. Background technique [0004] Cancer immunotherapy studies have now demonstrated promising clinical response rates in patients with melanoma and in subsets of patients with other solid tumors. Those studies have involved monoclonal antibody (MAb) checkpoint inhibitors (such as anti-CTLA4), anti-programmed cell death-1 (PD-1), and anti-programmed cell death-1 ligand (PD-L1), and cytokines such as IL-2 and IL-15. 1-5 [0005] Most antibodies against PD-1 / PD-L1 are IgG4 isotype, or IgG1 isotype engine...

Claims

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Application Information

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IPC IPC(8): A61K38/00A61K38/20A61P35/00C07K14/54C07K19/00C12N15/62
CPCA61K38/00A61P35/00C07K14/5443C07K2319/30C07K14/71C07K14/7155C07K2319/32C07K2319/74C07K16/2827C07K2317/622C07K2319/00C07K2317/32C07K16/244C07K16/2863C07K2317/53A61K38/1793C12N15/62C12P21/00A61K39/395
Inventor 李琼珍朱晓云H·C·黄
Owner 阿尔托生物科学有限责任公司
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