Antibodies for chelated radionuclides and clearing agents

A technology of scavenger and chelating agent, which is applied in the direction of radioactive carriers, radioactive preparations in vivo, antibodies, etc., and can solve problems such as unstable binding of radionuclides, slow complex formation rate, etc.

Pending Publication Date: 2021-04-09
オラノメッド +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, DOTA does not stably bind all radionuclides and can exhibit a slower rate of complex formation (Yong and Brechbiel, Dalton Trans 2001 June 21, 40(23):6068-6076)

Method used

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  • Antibodies for chelated radionuclides and clearing agents
  • Antibodies for chelated radionuclides and clearing agents
  • Antibodies for chelated radionuclides and clearing agents

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0868] Example 1: Description of Immunization

[0869] Immunization of Rabbits

[0870] The 2 enantiomers Pb-DOTAM-Alkyl-PEG 4 - A 1:1 mixture of KLH fractions (MS2-DOTAM KLH fraction 1 and MS2-DOTAMKLH fraction 2) for immunization of New Zealand white rabbits or transgenic rabbits containing human immunoglobulin loci, as in WO 2000 / 46251, WO 2002 / 12437, WO 2005 / 007696, WO 2006 / 047367, US 2007 / 0033661, and WO 2008 / 027986. Each rabbit was immunized with 500ug of the immunogen mixture emulsified in complete Freund's adjuvant by intradermal application on day 0 and 500ug each day by alternating intramuscular and subcutaneous application on days 7, 14, 28, 56 . Thereafter, rabbits received monthly subcutaneous immunizations of 500ug, and aliquots of blood were collected 7 days after immunization for serum titer determination. Larger blood samples (estimated 10% of total blood volume) were collected during month 3 of immunization and during month 9 (5-7 days after immunizati...

Embodiment 2

[0873] Example 2: Cloning B cells from rabbits

[0874] Isolation of Rabbit Peripheral Blood Mononuclear Cells (PBMC)

[0875] Blood samples were obtained from immunized rabbits. Whole blood containing EDTA was diluted twofold in 1x PBS (PAA, Pasching, Austria) followed by density centrifugation using mammalian lymphocytes (Cedarlane Laboratories, Burlington, Ontario, Canada) according to the manufacturer's instructions. PBMCs were washed twice with 1x PBS.

[0876] EL-4 B5 medium

[0877] Supplemented with 10% FCS (Hyclone, Logan, UT, USA), 2 mM Glutamin, 1% penicillin / streptomycin solution (PAA, Pasching, Austria), 2 mM sodium pyruvate, 10 mM HEPES (PAN Biotech, Aidenbach, Germany) and RPMI 1640 (Pan Biotech, Aidenbach, Germany) in 0.05 mM b-mercaptoethanol (Gibco, Paisley, Scotland).

[0878] coating of the board

[0879] Sterile cell culture 6-well plates were coated with 2 μg / ml KLH in carbonate buffer (0.1 M sodium bicarbonate, 34 mM sodium bicarbonate, pH 9...

Embodiment 3

[0889] Example 3: Expression of Rabbit Antibody

[0890] PCR amplification of V domains

[0891] Total RNA was prepared from B cell lysates (resuspended in RLT buffer, Qiagen, cat. no. 79216) using the NucleoSpin 8 / 96 RNA kit (Macherey & Nagel; 740709.4, 740698) according to the manufacturer's protocol. RNA was eluted with 60 μl of RNase-free water. cDNA was generated by reverse transcriptase reaction using 6 μl RNA using Superscript III first strand synthesis SuperMix (Invitrogen 18080-400) and oligo dT primers according to the manufacturer's instructions. Implement all steps on the Hamilton ML Star system. The primers rbHC.up and rbHC.do for heavy chain and rbLC.up and rbLC.do for light chain (Table 3) were amplified with AccuPrime Super Mix (Invitrogen 12344-040) using 4 μl cDNA in a final volume of 50 μl. Increased immunoglobulin heavy and light chain variable regions (VH and VL). All forward primers were specific for the signal peptide (VH and VL, respectively), whi...

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Abstract

The present application relates to antibodies which bind specifically to chelated radionuclides, including bispecific antibodies, It further relates to the use of such bispecific antibodies in applications such as radioimmunoimaging and radioimmunotherapy. It additionally relates to clearing agents and useful in such methods.

Description

[0001] Field of Invention [0002] The present application relates to antibodies, including bispecific antibodies, that specifically bind chelated radionuclides. The present application further relates to the use of such bispecific antibodies in applications such as radioimmunoimaging and radioimmunotherapy. The present application additionally relates to scavengers and compositions useful in such methods. [0003] Background of the Invention [0004] Monoclonal antibodies have been developed to target drugs to cancer cells. By conjugating toxic agents to antibodies that bind tumor-associated antigens, it has the potential to provide more specific tumor killing with less damage to surrounding tissues. [0005] In pretargeted radioimmunotherapy (PRIT), antibody constructs with affinity for tumor-associated antigens on the one hand and for radiolabeled compounds on the other hand are used. In the first step, the antibody is administered and localized within the tumor. Subsequ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/395A61K31/28C07K16/28C07K16/30C07K16/32C07K16/44A61K47/68A61P35/00A61K51/04
CPCC07K16/2887C07K16/3007C07K16/3069C07K16/32C07K16/44C07K2317/24C07K2317/31C07K2317/34C07K2317/52C07K2317/55C07K2317/64C07K2317/92C07K2317/94A61K51/0482A61K51/0495A61K2039/505A61K2039/545A61P35/00A61K47/61A61K51/065A61K51/1027A61K51/1048A61K51/1051
Inventor J·托格P·朱雷克F·罗哈斯-奎亚诺G·E·基弗O·弗雷塔格C·格德斯C·克莱因P·乌玛娜A·哈斯S·弗罗斯特A·赛迪T·纳亚克
Owner オラノメッド
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