Bispecific signaling agents and uses thereof

A signal transduction and specific technology, applied in the field of chimeric proteins, can solve problems such as failure of checkpoint inhibitory therapy, narrowing of patient treatment window, and susceptibility of patients to other diseases

Active Publication Date: 2018-12-21
ORIONIS BIOSCIENCES BV +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, despite impressive patient responses to agents targeting these co-stimulatory and co-inhibitory molecules, including, for example, the clinical trials that led to the approval of YERVOY, KEYTRUDA, and OPDIVO, checkpoint inhibitory therapies still fail in the vast majority of patients up
[0008] In addition, most cancer treatments, including immunotherapy, require complex regimens of various agents, each of which typically carries a complex pattern of side effects, thereby narrowing the patient's therapeutic window while on treatment and making the patient more susceptible to other diseases

Method used

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  • Bispecific signaling agents and uses thereof
  • Bispecific signaling agents and uses thereof
  • Bispecific signaling agents and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[1217] Example 1: Characterization of bispecific chimeras using an in vivo B16 melanoma model.

[1218] Anti-mouse PD-L1, anti-mouse CD20, anti-mouse Clec9A, and / or anti-mouse CD8 targeting moieties and a modified interferon signaling domain (i.e., mutant human interferon (IFN) α2-Q124R or R149A) engineered a variety of bispecific chimeric constructs. A list of such chimeric constructs is provided below. The in vivo activity of the chimeras was characterized using an in vivo B16 melanoma model.

[1219]

[1220] figure 1 Antitumor activity of anti-CD20 VHH-human IFNα(Q124R) mutant-anti-PD-L1 VHH bispecific constructs is shown using the B16 tumor model. In the experiment, C57BL / 6 mice were subcutaneously inoculated (50 μl) 6×10 5 B16mCD20cl1 melanoma tumor cells (a mouse melanoma cell line stably expressing mouse CD20). When the tumor reaches ±10mm 2 Peri-lesion treatments were initiated with 30 μg of each construct (100 μl) when the size (as measured by calipers) wa...

Embodiment 2

[1226] Example 2: Characterization of bispecific chimeras using the in vivo 4T1 breast tumor model

[1227] The antitumor activity of various monospecific and bispecific chimeric constructs was also tested using the 4T1 breast tumor model. In the experiments, mice were inoculated with 4T1 mammary tumor cells. Once tumors reached a certain size, mice were treated with monospecific anti-PD-L1 VHH or monospecific anti-PD-L1 VHH-human IFNα Q124R mutant construct. like Figure 8 As shown in panel A, anti-PD-L1 had no effect in the 4T1 breast tumor model, whereas the monospecific PD-L1-Q124R construct had antitumor activity.

[1228] Figure 8 Panel B shows a 4T1 breast tumor model study in which compared to co-administration of fusions of anti-Clec9A and modified human IFNα (Q124R) and fusions of anti-PD-L1 and modified human IFNα (Q124R) or co-administration Fusion of anti-Clec9A with modified human IFNα (Q124R) and anti-PD-L1 VHH, bispecific (anti-Clec9A and anti-PD-L1) fus...

Embodiment 3

[1230] Example 3: Use of bispecific chimeras and doxorubicin in B16 melanoma and 4T1 breast tumor models combination therapy

[1231] The antitumor effect of combination therapy with doxorubicin and bispecific constructs was examined. In one set of experiments, mice were transplanted with B16 cells (a mouse melanoma cell line stably expressing mouse CD20) to induce tumors. In a second set of experiments, mice were transplanted with 4T1 mammary tumor cells. Mice were then treated with a bispecific (anti-mouse Clec9A and anti-mouse PD-L1 ) fusion to modified human IFNα (Q124R) with or without doxorubicin. In a third set of experiments, mice were transplanted with 4T1 mammary tumor cells and subsequently treated with a bispecific (anti-CD8 and anti-PD-L1) fusion to modified human IFNα (Q124R) with or without doxorubicin. Treat with doxorubicin. like Figure 9 As shown in panels A to C, in all three tumor models, the combined bispecific chimera and doxorubicin compared wit...

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Abstract

The present invention relates, in part, to bispecific chimeric proteins that find use in various immunotherapies based on various properties, including, for example, a dual immune cell recruitment andimmune signal delivery function.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of the following U.S. Provisional Patent Application Numbers: 62 / 291,769 filed February 5, 2016; 62 / 335,880 filed May 13, 2016; 62 / 411,805 filed October 24, 2016; 62 / 291,772 filed February 5; 62 / 291,774 filed February 5, 2016; 62 / 335,965 filed May 13, 2016; 62 / 291,776 filed February 5, 2016; May 2016 62 / 335,968 filed on 13 May; 62 / 335,979 filed on May 13, 2016; 62 / 336,030 filed on May 13, 2016; 62 / 353,607 filed on June 23, 2016; and 5 February 2016 62 / 291,779 filed on , the entire contents of which are incorporated herein by reference in their entirety. technical field [0003] The present invention relates, in part, to chimeric proteins that can recruit effector cells and transmit signaling to provide beneficial effects. [0004] Description of Text Files Submitted Electronically [0005] The contents of the text file electronically filed with this article are hereby incorporated b...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/28
CPCA61K38/00A61K39/395C07K14/7156C07K16/00C07K16/249C07K16/2818C07K16/2827C07K16/2851C07K16/2887A61K2039/505A61K2039/57C07K2317/31C07K2317/33C07K2317/622C07K2317/66C07K2317/90C07K2319/00C07K16/2815A61P35/00A61P25/28C07K14/56C07K2317/569C07K2317/74Y02A50/30C07K2317/22C07K2317/24C07K2317/92C07K2319/02C07K2319/33C07K2319/735C07K2319/74
Inventor N·克雷J·塔威尼尔S·范林特A·考威尔
Owner ORIONIS BIOSCIENCES BV
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