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Antiangiogenic agents and aldesleukin

A kind of aldesleukin and anti-vascular technology, applied in cardiovascular system diseases, anti-tumor drugs, peptide/protein components, etc.

Inactive Publication Date: 2008-03-19
CHIRON CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Targeting angiogenic mechanisms through pathways other than vascular endothelial growth factor-mediated pathways may also be effective in kidney cancer

Method used

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  • Antiangiogenic agents and aldesleukin
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  • Antiangiogenic agents and aldesleukin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0332] Compositions co-administered with rIL-2

[0333] A. Compound

[0334] Table 1: Quinazoline Examples

[0335]

[0336] Table 2: Indolinone compounds

[0337]

[0338] Table 3: Other compounds

[0339]

[0340]

[0341] Table 4: Macrocyclic compounds

[0342]

[0343] Table 5: Isoindoline compounds

[0344]

[0345] B. Synthesis

[0346] Quinazoline

[0347] Case 1:

[0348]

[0349]Scheme 1 describes a modular approach to the synthesis of multiple substituted quinazoline compounds. AG refers to an activating group such as halogen, triflate or ketone, in which up to 4 AG groups may be present. Since the 4-chloro position shown in the third step is more active than positions 5-8 on the benzyl ring, the substitution of NHRR' is unlikely to simultaneously replace AG at any position 5-8. Subsequently, the last step of substituting R" for the AG group can be carried out in the presence of a weak-to-moderate base. Alternatively, the AG group can be modified to produce...

Embodiment 2

[0373] Preparation of rIL-2

[0374] Aldesleukin, rIL-2 (NSC3773364) (Proleukin _ , Chiron): The messenger RNA of the human Jurkat cell line was used to produce double-stranded cDNA, which was hybridized to the pBR322 plasmid. Use the one corresponding to the short IL-2 basic sequence 32 The p-labeled oligonucleotide probe identifies clones containing the IL-2 gene. Insert the gene into a region of the pBR322 plasmid with convenient restriction sites. Insert a suitable promoter and ribosome binding site before the IL-2 gene, and the resulting expression clone encodes a modified recombinant rIL-2. Cysteine ​​at position 125 was conservatively substituted with serine by cloning IL-2 in vitro mutagenesis. The obtained molecule is indistinguishable from natural IL-2 in terms of in vitro biological activity. Culture the E. coli production strain carrying the aldesleukin gene in the fermentor. The culture was harvested, and aldesleukin was extracted. A series of chromatography steps are...

Embodiment 3

[0378] Comparison of treatment with rIL-2 composition alone and combined treatment with rIL-2 composition and anti-angiogenesis agent Table 6 summarizes the results of high-dose rIL-2.

[0379] Table 6: Clinical trials of a single drug rIL-2 bolus injection program 1

[0380] Author

Scheme rIL-2

Dose range

(MIU)

Number of patients

CR

PR

Median duration of response

/ Median survival rate (mos)

Atkins and others (7)

Q8 hours 1-5 days

24 / m 2

71

4

8

16+ / 15.5

Fyfe et al (8)

Q8 hours 1-5 days

0.6-0.72 / kg

255

12

24

20.3 / 16.3

Yang et al (9)

Q8 hours 1-5 days

0.72 / kg

65

2

11

NS

Rosenberg et al (10)

Q8 hours 1-5 days

Q8 hours 1-5 days

0.072 / kg

0.72 / kg

60

149

4

10

5

20

NS

15 / 20

Rosenberg et al (11)

Q8 hours 1-5 days

0.72 / kg

48

4

6

NS

Taneja and others (12)

Q8 hours 1-5 days

...

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PUM

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Abstract

The present invention relates to combination therapies with IL-2 compositions and antiangiogenic agents for the treatment of cancer. Further provided are methods of alleviating toxicities and increasing the efficacy associated with the administration of IL-2 compositions or antiangiogenic compositions.

Description

[0001] Cross reference of related applications [0002] According to 35 U.S.C. §119(e), this application claims the priority of provisional application 60 / 654,341 filed on February 18, 2005, and the entire application is incorporated herein by reference. Invention field [0003] The present invention relates to a treatment method for diseases related to abnormal cell proliferation. In some embodiments, recombinant IL-2 is used in combination with anti-angiogenesis agents to treat cancer. Background of the invention [0004] Capillaries extend into almost all human tissues, provide oxygen and nutrients for the tissues, and take away waste products. Under normal conditions, the endothelial cells lining capillaries do not divide. Therefore, the number or size of capillaries in an adult does not usually increase. However, under certain conditions, such as tissue damage or at a certain stage of the menstrual cycle, capillaries begin to proliferate rapidly. This process of forming new c...

Claims

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Application Information

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IPC IPC(8): A61K38/20A61K31/502A61K31/517A61K31/404A61K31/4412A61P35/00
CPCA61K31/4412A61K31/502A61K31/404A61K38/2013A61K31/517A61P9/00A61P9/02A61P9/12A61P35/00A61P37/04A61P43/00A61K2300/00A61K38/20
Inventor S·L·奥科曼K·丹尼-麦斯L·埃利亚斯B·加莱D·梅内赛斯G·W·威瑟雷尔
Owner CHIRON CORP
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