NU 2016-048

Inventors

Milan Mrksich*

Justin Modica

Short Description

A novel method to join antibody fragments to produce megamolecule antibody-like drugs

Abstract

Northwestern researchers have developed a novel Lego-like platform to build megamolecule antibodies whose fragments can be customized for particular targets.  The development of biologic drugs, specifically monoclonal antibodies (mAbs) has gained much momentum due to their ability to specifically target disease-related proteins in circulation and on cell surfaces.  Thus, the industry has focused on developing a ‘next-generation antibody’ with enhanced therapeutic potential.  Efforts to increase the valency of antibodies, increase cytotoxicity and half-life of antibodies, and direct the immune system toward clearing targets have been common strategies to increase the therapeutic potential of mAbs. The engineered mAbs, however, have often faced challenges with high-yield production and synthetic flexibility that permits a desired function to be systematically optimized. Northwestern researchers developed a novel method of joining antibody fragments and antibody-like fragment-fusion proteins in a modular fashion using small molecule linkers that react site-specifically in high yield.  This novel modular process is rapid and can be carried out under mild reaction conditions, permitting not only scalable preparation of molecules with molecular weights greater than 250 kDa, but also allowing the creation of an incredibly diverse library of antibody-like drugs with altered valency, stoichiometry, geometry, orientation and effector function.  This unique method offers a new route to generate precisely defined structures that are too large to be prepared by current strategies in a precise and cost-efficient manner. 

Applications

• Antibody-drug conjugates
• Bispecific antibodies
• Immunomodulatory agents
• Enhanced targeting agents
• Contrast agents for medical imaging

Advantages

• Increases yield of antibody production
• Offers ability to bind a diverse set of effector molecules
• Retains pharmacological stability of the parent molecule
• Produces homogeneous populations of antibody products
• Requires less optimization prior to scale-up, diminishing cost of production

Publications

Modica J, Skarpathiotis S, Mrksich M (2012). Modular assembly of protein building blocks to create precisely defined megamolecules. ChemBioChem 13:2331-2334.

IP Status

US provisional patent applications have been filed.