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1. WO2018015213 - SITE-SPECIFIC CONJUGATION TO ANTIBODY LYSINE RESIDUES WITH SOLID-PHASE IMMOBILIZED MICROBIAL TRANSGLUTAMINASE MTG AND MTG IN SOLUTION

Publication Number WO/2018/015213
Publication Date 25.01.2018
International Application No. PCT/EP2017/067403
International Filing Date 11.07.2017
IPC
A61K 47/64 2017.01
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
47Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
50the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
51the non-active ingredient being a modifying agent
62the modifying agent being a protein, peptide or polyamino acid
64Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
A61K 47/68 2017.01
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
47Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
50the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
51the non-active ingredient being a modifying agent
68the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
C12N 11/08 2006.01
CCHEMISTRY; METALLURGY
12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
11Carrier-bound or immobilised enzymes; Carrier-bound or immobilised microbial cells; Preparation thereof
02Enzymes or microbial cells immobilised on or in an organic carrier
08the carrier being a synthetic polymer
CPC
A61K 47/60
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
47Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
50the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
51the non-active ingredient being a modifying agent
56the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
59obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
60the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
A61K 47/64
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
47Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
50the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
51the non-active ingredient being a modifying agent
62the modifying agent being a protein, peptide or polyamino acid
64Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
A61K 47/6803
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
47Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
50the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
51the non-active ingredient being a modifying agent
68the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
6801Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
6803Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
A61K 47/6811
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
47Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
50the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
51the non-active ingredient being a modifying agent
68the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
6801Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
6803Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
6811the drug being a protein or peptide, e.g. transferrin or bleomycin
A61K 47/6887
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
47Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
50the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
51the non-active ingredient being a modifying agent
68the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
6835the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
6887Antibody-chelate conjugates using chelates for therapeutic purposes
A61K 47/6937
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
47Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
50the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
69the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
6921the form being a particulate, a powder, an adsorbate, a bead or a sphere
6927the form being a solid microparticle having no hollow or gas-filled cores
6929the form being a nanoparticle, e.g. an immuno-nanoparticle
6931the material constituting the nanoparticle being a polymer
6935the polymer being obtained otherwise than by reactions involving carbon to carbon unsaturated bonds, e.g. polyesters, polyamides or polyglycerol
6937the polymer being PLGA, PLA or polyglycolic acid
Applicants
  • PAUL SCHERRER INSTITUT [CH]/[CH]
Inventors
  • SPYCHER, Philipp René
  • BEHE, Martin
  • SCHIBLI, Roger
  • HURWITZ, David
Agents
  • FISCHER, Michael
Priority Data
16180382.020.07.2016EP
Publication Language English (EN)
Filing Language English (EN)
Designated States
Title
(EN) SITE-SPECIFIC CONJUGATION TO ANTIBODY LYSINE RESIDUES WITH SOLID-PHASE IMMOBILIZED MICROBIAL TRANSGLUTAMINASE MTG AND MTG IN SOLUTION
(FR) CONJUGAISON SITE-SPÉCIFIQUE SUR DES RÉSIDUS LYSINE D'ANTICORPS À L'AIDE D'UNE TRANSGLUTAMINASE MICROBIENNE MTG IMMOBILISÉE EN PHASE SOLIDE, ET D'UNE MTG EN SOLUTION
Abstract
(EN)
Site-specific modification of proteins with microbial transglutaminase (MTG) is a powerful and versatile strategy for a controlled modification of proteins under physiological conditions. We present evidence that solid-phase microbead- immobilization can be used to site-specifically and efficiently attach different functional molecules important for further downstream applications to proteins of therapeutic relevance including scFV, Fab-fragment and antibodies. We demonstrate that MTG remained firmly immobilized with no detectable column bleeding and that enzyme activity was sustained during continuous operation, which allowed for a convenient recycling of the enzyme, thus going beyond solution-phase MTG conjugation. In addition it is showed that immobilized MTG shows enhanced selectivity towards a certain residue in the presence of several reactive residues which are all targeted if the conjugation was carried out in solution. It is also reported on the site-specific lysine conjugation of antibodies using potent glutamine containing peptides with immobilized and MTG in solution. In addition, the generation of dual site-specifically conjugated IgG1 with immobilized and MTG in solution is reported, i.e. site-specific conjugation to glutamine and lysine residues of IgG1 antibody. Site-specific glutamine conjugation with small peptides containing a lysine residue and a functional moiety is also described.
(FR)
La modification site-spécifique de protéines à l'aide d'une transglutaminase microbienne (MTG) est une stratégie puissante et polyvalente pour la modification contrôlée de protéines dans des conditions physiologiques. Nous avons apporté des preuves montrant que l'immobilisation de microbilles en phase solide peut être utilisée pour lier efficacement et de façon spécifique au site diverses molécules fonctionnelles, importantes pour des applications supplémentaires en aval, à des protéines présentant une pertinence thérapeutique, lesquelles comprennent le scFV, les fragments Fab et les anticorps. Nous avons démontré que la MTG restait fermement immobilisée sans perte détectable au niveau de la colonne et que l'activité enzymatique était maintenue lors d'un fonctionnement en continu, ce qui permet un recyclage pratique de l'enzyme, allant ainsi au-delà de la conjugaison de la MTG en phase solution. En outre, il a été montré que la MTG immobilisée présentait une sélectivité améliorée envers un résidu donné en présence de plusieurs résidus réactifs, lesquels sont tous ciblés si la conjugaison est réalisée en solution. L'invention décrit également la conjugaison spécifique au site d'anticorps au niveau de résidus lysine par l'utilisation de peptides puissants contenant de la glutamine avec une MTG immobilisée et une MTG en solution. De plus, l'invention décrit la génération d'IgG1 doublement conjugué de façon site-spécifique par une MTG immobilisée et en solution, ceci correspondant à la conjugaison spécifique au site de résidus glutamine et lysine de l'anticorps IgG1. L'invention concerne également la conjugaison spécifique au site au niveau de la glutamine avec de petits peptides contenant un résidu lysine et une partie fonctionnelle.
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