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Targeting of ERB antigens

A technology of antigens and antibodies, applied in the direction of antibodies, instruments, analysis materials, etc., can solve problems such as competition

Inactive Publication Date: 2007-01-31
米特拉医药股份公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0047] However, in most cases the same type of functional group of the antibody (ε-amino group) is used to couple the chelating and biotin groups, resulting in competition for the most accessible sites

Method used

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  • Targeting of ERB antigens
  • Targeting of ERB antigens
  • Targeting of ERB antigens

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0151] Example 1: Conjugation and radiolabeling of trastuzumab

[0152] In this and subsequent examples, indium-111 was used in some instances in place of yttrium-90 because the former is a gamma-radiating source and has less radiation hazard than yttrium-90. The monoclonal antibody trastuzumab was mixed with 3-(13'-thioureabenzyl-DOTA)trioxadiamine-1-(13"-biotin-Asp-OH)trioxadiamine-5-iso Thiocyanate-aminoisophthalate (MitraTag TM -1033) (hereinafter also referred to simply as 1033) was conjugated using the method described by Wilbur D.S et al. in Bioconjuagte Chem. 13: 1079-1092, 2002. 10 mg of monoclonal antibody was dialyzed against 1 liter of metal-free HEPES at 4°C for 3 days with 3 buffer changes. Preparation of MitraTag TM Aqueous solution of -1033 (800μg), added to the antibody solution. After overnight incubation at room temperature, the antibody conjugate was dialyzed against 1 liter of metal-free 250 mM acetate buffer (pH 5.3) at 4° C. for 4 days with a minimum...

Embodiment 2

[0154] Example 2: Binding of 1033-conjugated trastuzumab to avidin adsorbent

[0155] Analysis of microcolumns bound to the avidin sorbent employed in the MitraDep(R) device 111 In-labeled 1033-trastuzumab radioconjugate fraction. About 97% of the radioactivity in the radiolabeled 1033-conjugate sample was bound to the microcolumn by the avidin sorbent.

Embodiment 3

[0156] Example 3: Affinity Analysis of Binding to Target Antigen

[0157] The effect of the conjugation process on the affinity (strength) of trastuzumab to the target antigen was studied using a competitive inhibition assay. Briefly, increasing amounts of trastuzumab were combined with constant amounts of 111 In-labeled 1033-trastuzumab mix. Add the mixture to fixed SK-BR3 cells in a 96-well plate. After 2 hours of incubation at room temperature, the wells were washed and the radioactivity bound to cells was measured in an automated NaI(T1) scintillation cytometer.

[0158] The amount of radioactivity bound was plotted against the concentration of trastuzumab ( figure 1 ), calculate the concentration required for 50% inhibition (IC 50 ). IC 50 is a measure of the relative affinity of the antibodies tested; a decrease in affinity is seen as the IC 50 Concentration increases. Significant changes in affinity usually indicate IC 50 The difference should be at least 10-fo...

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Abstract

A conjugate comprising a) a trifunctional cross-linking moiety, to which is coupled b) an affinity ligand via a linker 1, c) a cytotoxic agent, optionally via a linker 2, and d) an anti Erb antibody or variants thereof having the ability to bind to Erb antigens expressed on mammalian tumour surfaces with an affinity-binding constant of at least 5x10<6>M<-1>, wherein the affinity ligand is biotin, or a biotin derivative having essentially the same binding function to avidin or streptavidin as biotin, wherein stability towards enzymatic cleavage of the biotinamide bond has been introduced in linker 1.

Description

[0001] invention technical field [0002] The present invention relates to novel conjugates that bind to mammalian Erb gene products and pharmaceutical compositions comprising said conjugates, to kits comprising such pharmaceutical compositions and in vitro devices, and to therapeutic and / or diagnostic expression of Erb Gene product cancer approach. Background technique [0003] Proto-oncogenes encoding growth factors and their receptors drive the development of breast cancer and other human malignancies (Aronson, SA, Science, 254:1146-1153 (1991)) and thus are potential targets for new therapeutic strategies. Specifically, increased expression of this gene has been observed in more dangerous breast, bladder, lung and gastric cancers. [0004] Human epidermal growth factor receptor-2 (HER2) encodes a cell surface receptor and is involved in signal transduction pathways leading to normal cell growth and differentiation (DiAgustine R & Richards RG, J. Mammary Gland Biol Neoplas...

Claims

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Application Information

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IPC IPC(8): A61K39/395A61K51/10G01N33/543C07K17/02
Inventor B·E·B·桑德伯格R·尼尔松
Owner 米特拉医药股份公司
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