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Treatment strategies for immune-response disorders by using Fc receptor polymorphisms as diagnostics

An immunotherapeutic, individual technology for use in predictive medicine that addresses issues such as reduced ability to interact

Inactive Publication Date: 2007-02-07
CHIRON CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Thus, homozygous FcγRIIIA 48L / L, FcγRIIIA 158F / F, or FcγRIIA 131R / R have reduced ability to interact with specific IgG subclasses

Method used

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  • Treatment strategies for immune-response disorders by using Fc receptor polymorphisms as diagnostics
  • Treatment strategies for immune-response disorders by using Fc receptor polymorphisms as diagnostics
  • Treatment strategies for immune-response disorders by using Fc receptor polymorphisms as diagnostics

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0196] The art provides basic guidance for the preparation and use of polypeptide variants. During the preparation of IL-2 variants, those skilled in the art can easily determine which modification of the nucleotide or amino acid sequence of the native protein will result in the production of IL-2 suitable for use as a therapeutically active component in the pharmaceutical composition of the method of the present invention. Variants.

[0197] IL-2 or variants thereof for use in the methods of the invention may be of any origin, but are preferably produced recombinantly. "Recombinant IL-2" or "recombinant IL-2 variant" refers to a biological activity comparable to that of native sequence IL-2 and described by, for example, Taniguchi et al., (1983), Nature, 302:305-310 and Devos, (1983) , Interleukin-2 or its variants prepared by recombinant DNA technology described in Nucleic Acids Research, 11: 4307-4323; or IL-2 changed by mutation as described in Wang et al., (1984), Scienc...

Embodiment 1

[0228] Example 1: Materials and methods

[0229] A.IL-2

[0230] The IL-2 formulation used was manufactured by Chiron Corporation of Emeryville, California under the trade name Proleukin  . IL-2 in this formulation is a recombinantly produced, unglycosylated IL-2 mutein called aldesleukin, which has the initial alanine residue deleted and cysteine ​​residue 125 replaced with a serine residue ( Known as de-alanyl-1, serine-125 human interleukin-2) and the amino acid sequence of natural human IL-2 is different. The IL-2 mutein was expressed in E. coli and purified by diafiltration and ion exchange chromatography as described in US Pat. No. 4,931,543. IL-2 preparations with Proleukin  Provided under the trade name, it is a sterile, white to off-white preservative-free lyophilized powder, containing 1.3mg protein (22MIU) per vial.

[0231] B. Anti-CD20 Antibody

[0232] The anti-CD20 antibody used in this example and the following examples is Rituxan  (Rituximab; IDEC-C2...

Embodiment 2

[0247] Example 2: Combination of IL-2-rituximab in a xenograft model of human B-cell non-Hodgkin's lymphoma

[0248] IL-2 was evaluated in two different xenograft models of human B-cell lymphoma (Proleukin  ) in combination with rituximab. See, eg, the Namalwa and Daudi xenograft models described by Hudson et al., (1998), Leukemia, 12(12):2029-2033.

[0249] feature

Namalwa

Daudi

CD20 expression

Low

high

disease state

Aggressive

B

Efficacy of rituximab

tolerance

Responsive

Efficacy of IL-2

efficient

Low curative effect

model duration

Two weeks

6 weeks

[0250] Namalwa or Daudi tumor cells were implanted into mice when the tumor was 100-200mm 3 During the phase, rituximab and / or IL-2 is usually administered 8-12 days after tumor cell implantation.

[0251] The following is a single drug dosage regimen. One group of mice received 0.25 mg / kg of IL-2 subcutaneously (s.c.) p...

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Abstract

The present invention provides diagnostic methods utilizing Fc gamma receptor (Fc gamma R) polymorphisms as interleukin-2 (IL-2) immunotherapeutic intervention. The method includes detecting the allelic pattern of the FcγRIIIA gene or the FcγRIIA gene in an individual and determining whether the allelic pattern predicts a positive therapeutic response to IL-2 immunotherapy. Presence of FcγRIIIA 158F / F homozygous genotype, and / or presence of one or two copies of FcγRIIIA 48L allele, and / or presence of one or two copies of FcγRIIA 131RL allele predicts immunity to IL-2 The treatment had a positive therapeutic response, thus suggesting that IL-2 immunotherapy can be used as a medical intervention for the treatment of immune diseases. The diagnostic method can be used to identify individuals, especially those with cancer, who can improve their immune function through IL-2 immunotherapy.

Description

field of invention [0001] The present invention relates to the field of predictive medicine, and more particularly relates to the use of Fcγ receptor (FcγR) polymorphisms as a diagnostic method for evaluating treatment options for immune response diseases. Background of the invention [0002] Interleukin-2 (IL-2) is a potent stimulator of natural killer (NK) and T-cell proliferation and function (Morgan et al. (1976), Science 193:1007-1011). This naturally occurring lymphokine has been shown to have antitumor activity against various malignancies alone or in combination (use) with lymphokine-activated killer (LAK) cells or tumor infiltrating lymphocytes (TIL) (see, e.g., Rosenberg et al., (1987) , N.Engl.J.Med., 316:889-897; Rosenberg, (1988), Ann.Surg., 208:121-135; Topalian et al., (1988), J.Clin.Oncol.6:839- 853; Rosenberg et al., (1988), N. Engl. J. Med., 319:1676-1680; and Weber et al., (1992), J. Clin. Oncol., 10:33-40). Proleukin has been...

Claims

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Application Information

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IPC IPC(8): C12Q1/68A61K38/19C07H21/04
Inventor S·E·威尔逊
Owner CHIRON CORP
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