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Regulating chimeric antigen receptors

一种嵌合抗原受体、配体的技术，应用在癌抗原成分、抗体医疗成分、抗体模拟物/支架等方向

Pending Publication Date: 2020-07-07
DANA FARBER CANCER INST INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, Jensen and Riddell note that using this approach is challenging due to uncertainties in CAR activation in the presence of small molecules and potential toxicity issues related to strategies such as
[0017] WO2016 / 200822 by Axiomx, Inc. entitled "Methods and Compositions for Producing a Chimeric Polypeptide" describes the use of mitotic and small molecules (such as rapamycin or rapamycin analogs) to transform chimeric antigens into body sequestration to intracellular regions, such as mitochondria, thereby rendering CAR ineffective

Method used

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  • Regulating chimeric antigen receptors
  • Regulating chimeric antigen receptors
  • Regulating chimeric antigen receptors

Examples

Experimental program
Comparison scheme
Effect test

Synthetic example 1

[1820] Synthesis Example 1: Synthesis of dBET1

[1821]

[1822] (1) Synthesis of JQ-acid

[1823] JQ1 (1.0 g, 2.19 mmol, 1 equiv) was dissolved in formic acid (11 mL, 0.2M) at room temperature and stirred for 75 hours. The mixture was concentrated under reduced pressure to give a yellow solid (0.99 g, quantitative yield), which was used without purification. 1 H NMR (400MHz, methanol-d 4 )δ7.50–7.36(m,4H),4.59(t,J=7.1Hz,1H),3.51(d,J=7.1Hz,2H),2.70(s,3H),2.45(s,3H), 1.71 (s,3H). LCMS 401.33 (M+H).

[1824] N-(4-aminobutyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-oxoisoindoline-4 was synthesized according to a previously published method -yl)oxy)acetamide trifluoroacetate (Fischer et al., Nature 512(2014):49).

[1825] (2) Synthesis of dBET1

[1826] At room temperature, JQ-acid (11.3 mg, 0.0281 mmol, 1 eq) and N-(4-aminobutyl)-2-((2-(2,6-dioxopiperidin-3-yl)- 1,3-Oxoisoindolin-4-yl)oxy)acetamide trifluoroacetate (14.5 mg, 0.0281 mmol, 1 equiv) was dissolved in DMF (0.28 ...

Synthetic example 2

[1827] Synthesis Example 2: Synthesis of dBET4

[1828]

[1829]At room temperature, 0.1M N-(4-aminobutyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-oxoisoindoline- A solution of 4-yl)oxy)acetamide trifluoroacetate in DMF (0.438 mL) was added to (R)-JQ-acid (prepared from (R)-JQ1 in a similar manner to JQ-acid) (14.63 mg , 0.0365mmol, 1 equivalent) 0.0438mmol 1.2 equivalent). DIPEA (19.1 μl, 0.1095 mmol, 3 eq) and HATU (15.3 mg, 0.0402 mmol, 1.1 eq) were added and the mixture was stirred for 24 h, then diluted with MeOH and concentrated under reduced pressure. The crude material was purified by preparative HPLC to give a yellow solid (20.64 mg, 0.0263 mmol, 72%). 1 H NMR (400MHz, methanol-d 4 )δ7.79(dd, J=8.4,7.4Hz,1H),7.51(d,J=7.3Hz,1H),7.47–7.39(m,5H),5.11–5.06(m,1H),4.75(s ,2H),4.68(dd,J=8.8,5.5Hz,1H),3.47–3.31(m,5H),2.83–2.65(m,7H),2.44(s,3H),2.13–2.06(m,1H ),1.68(s,3H),1.67–1.60(m,4H). 13 C NMR (100MHz, cd 3 od)δ174.43,172.40,171.29,169.92,168.24,167.82,166.71,156.31,...

Synthetic example 3

[1830] Synthesis Example 3: Synthesis of dBET3

[1831]

[1832] At room temperature, 0.1M N-(2-aminoethyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-oxoisoindoline-4 A solution of -yl)oxy)acetamide trifluoroacetate in DMF (0.475 mL, 0.0475 mmol, 1.2 equiv) was added to Q-acid (15.86 mg, 0.0396 mmol, 1 equiv). DIPEA (20.7 μL, 0.1188 mmol, 3 equiv) and HATU (16.5 mg, 0.0435 mmol, 1.1 equiv) were then added and the mixture was stirred for 24 hours before purification by preparative HPLC to give a yellow solid (22.14 mg, 0.0292 mmol, 74%). 1 H NMR (400MHz, methanol-d 4 )δ7.82–7.75(m,1H),7.52–7.32(m,6H),5.04(dd,J=11.6,5.5Hz,1H),4.76(d,J=3.2Hz,2H),4.66(d ,J=6.6Hz,1H),3.58–3.35(m,6H),2.78–2.58(m,6H),2.48–2.41(m,3H),2.11–2.02(m,1H),1.70(d,J =11.8Hz, 3H). 13 C NMR (100MHz, cd 3 od)δ174.38,171.26,171.19,170.26,168.86,168.21,167.76,166.72,156.27,153.14,138.44,138.36,138.19,134.87,133.71,132.31,131.57,131.51,129.90,129.86,121.81,119.36,117.95,69.48, 54.83, 50.52, 40.09, 39.76, 38.30,...

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Abstract

This invention is in the area of compositions and methods for regulating chimeric antigen receptor immune effector cell, for example T-cell (CAR-T), therapy to modulate associated adverse inflammatoryresponses, for example, cytokine release syndrome and tumor lysis syndrome, using targeted protein degradation.

Description

[0001] Related applications [0002] This application claims the benefit of Provisional U.S. Application No. 62 / 456,649, filed February 8, 2017, and Provisional U.S. Application No. 62 / 457,124, filed February 9, 2017. The entire contents of these applications are hereby incorporated by reference for all purposes. [0003] incorporated by reference [0004] The contents of the text file named "16010-024WO1_sequencelisting_projectfile_ST25.txt" was created on January 24, 2018 and is 360 kilobytes in size, which is hereby incorporated by reference in its entirety. technical field [0005] The purpose of the present invention is to regulate CAR-T cell or TCR-T cell activation by allowing regulation of CAR or TCR expression in chimeric antigen receptor (CAR) or engineered T cell receptor (TCR) in response to associated side effects , such as off-target effects and inflammatory responses, such as cytokine release syndrome and tumor lysis syndrome, contain regulatable and targetabl...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04C07D401/14C07D487/04C07D495/04C07D495/14C07J43/00C12N5/10C07K19/00C12N9/90C12N9/10C07K14/535C07K14/705C07K14/725C07K16/28C07K16/32C12N5/0783A61K35/17A61K38/52A61K39/00A61K45/06A61P35/02A61P37/06
CPCC07D401/14C07K14/7051C07D487/04C12Y502/01008C12N9/104C12N9/90C07K2319/03C07K2319/20C07K2319/70C07K2319/95C07K16/2803C07K16/2896C07K2317/622C07K2317/73C07K2319/33C07D401/04C07D495/14A61K45/06A61P35/02A61K39/4611A61K39/464412A61K2239/48A61K2239/31C12N5/0636C12N5/0638A61K39/4631A61K39/464406A61K39/464426A61K39/464417A61P37/06A61K35/17A61K38/52C07D495/04C07J43/003C07K14/535C07K14/70517C07K14/70521C07K14/70578C07K16/2878C07K16/32C07K2317/76C07K2319/02C07K2319/30
Inventor J·布拉德纳J·罗伯茨B·纳贝特G·温特A·J·菲利普斯T·P·赫弗南D·巴克利
Owner DANA FARBER CANCER INST INC
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