Transglutaminase Conjugation Method and Linker

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This invention introduces a novel enzymatic method for creating antibody-payload conjugates (such as antibody-drug conjugates, ADCs) using microbial transglutaminase (MTG). It specifically provides specially designed linkers that facilitate efficient, site-specific conjugation to antibodies at select glutamine (Gln) residues—particularly Q295—without requiring deglycosylation or genetic modification. The method works with glycosylated (native) antibodies and supports incorporation of a wide range of payloads (e.g., drugs, imaging agents, radionuclides) and allows dual or multiple payload attachments. The resulting products are homogeneous, stoichiometrically defined, and retain antibody stability and functionality.

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• Production of site-specifically conjugated antibody-drug conjugates (ADCs) for cancer therapy, targeting malignant cells with potent toxins.
• Development of antibody conjugates for autoimmune or inflammatory disease therapies, delivering immunoregulatory agents site-specifically.
• Creation of highly uniform antibody-imaging agent conjugates for precise molecular and cellular imaging (e.g., PET, fluorescent or dual-modality imaging).
• Preparation of dual-labeled antibodies carrying two different drugs, overcoming cancer resistance or enabling combinatorial targeting strategies.
• Generation of antibody conjugates for targeted delivery of radionuclides in radioimmunotherapy.
• Manufacturing of diagnostic agents that require precise payload positioning to preserve antibody binding and pharmacokinetics.

BenefitsContent extracted from patent full text and abstract with AI.

• Enables site-specific conjugation to glycosylated (native) antibodies without need for deglycosylation or genetic engineering, preserving antibody function and regulatory compliance.
• Low heterogeneity: Produces well-defined, homogeneous conjugates with stable drug-to-antibody ratios and precise functional properties.
• Broad payload compatibility: Linker design allows coupling of a wide range of molecules (toxins, dyes, radionuclides, enzymes, nucleic acids, etc.), including simultaneous dual-payload attachment.
• Simple, efficient manufacturing: Rapid conjugation process (24–36 hours), high yields, fewer purification steps, and compatibility with off-the-shelf antibodies and payloads.
• Maintains immunomodulatory properties and native stability of antibodies, as glycosylation is retained.
• Enhances in vivo therapeutic index and pharmacokinetic profiles by reducing off-target effects and batch-to-batch variability.
• Improves cost-effectiveness and scalability for both research and commercial drug product development.

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Patent Abstract

The present invention relates to a method for generating an antibody-payload conjugate by means of a microbial transglutaminase (MTG). The method comprises a step of conjugating a linker having a primary amine residue, said linker having the peptide structure (shown in N->C direction) (Aax)m-(Aax)(NH2)-(Aax)n-B-(Aax)o, or (Aax)m-B-(Aax)n-(Aax)(NH2)-(Aax)o, to a G1n residue comprised in the heavy or light chain of an antibody. Aax(NH2) is an amino acid, amino acid derivative or amino acid mimetic comprising a side chain having a primary amine group (Fig. 1).