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Antibodies for chelated radionuclides

A bispecific antibody, antibody technology, applied in the field of scavengers and compositions, bispecific antibodies, can solve the problems of slow complex formation rate, unstable binding of radionuclides, etc.

Pending Publication Date: 2021-01-22
F HOFFMANN LA ROCHE & CO AG
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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
  • Antibodies for chelated radionuclides
  • Antibodies for chelated radionuclides

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0866] Example 1: Description of Immunization

[0867] Immunization of Rabbits

[0868] The 2 enantiomers Pb-DOTAM-Alkyl-PEG 4 - 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 immunization...

Embodiment 2

[0871] Example 2: Cloning B cells from rabbits

[0872] Isolation of Rabbit Peripheral Blood Mononuclear Cells (PBMC)

[0873] Blood samples were obtained from immunized rabbits. Whole blood containing EDTA was diluted two-fold with 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.

[0874] EL-4 B5 medium

[0875] 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).

[0876] coating of the board

[0877] 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...

Embodiment 3

[0887] Example 3: Expression of Rabbit Antibody

[0888] PCR amplification of V domains

[0889] 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. Primers rbHC.up and rbHC.do for heavy chain and rbLC.up and rbLC.do for light chain (Table 3) were amplified using 4 μl cDNA in a final volume of 50 μl with AccuPrime Super Mix (Invitrogen 12344-040) Immunoglobulin heavy and light chain variable regions (VH and VL). All forward primers were specific for the signal peptide (VH and VL, respectively), while the reverse ...

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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 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 tissue. [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. Subseque...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/395A61K31/28C07K16/28C07K16/30C07K16/32C07K16/44A61K47/68A61P35/00
CPCC07K16/2887C07K16/3007C07K16/32C07K16/44C07K2317/24C07K2317/31C07K2317/34C07K2317/52C07K2317/64C07K2317/92C07K2317/94A61K39/39558A61K51/0495A61K51/109A61K51/1096A61K2039/505A61K2039/545A61P35/00A61K2300/00C07K2317/565C07K2317/55C07K2317/71
Inventor C·克莱恩P·乌玛娜A·哈斯B·韦瑟F·利普斯梅尔G·乔治S·芬恩J·莫勒肯F·波曼D·马奇切科
Owner F HOFFMANN LA ROCHE & CO AG
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