Engineering Bispecific Antibodies to Cross the Blood-brain Barrier

Over the past decades, the development and regulatory approval of antibody-based therapeutics has progressed rapidly. But poor blood-brain barrier permeability has hampered the progress of effective antibody therapies for conditions in which the target is located in the central nervous system or CNS, which includes the brain.

One reason for this delayed progress is that the blood-brain barrier is a dynamic filtering mechanism that separates the brain from the circulatory system that carries blood to the brain and spinal cord tissue.

A complex interplay
The blood-brain barrier is formed from highly specialized endothelial cells that line the brain capillaries. Its structure and function dependent on the complex interplay between endothelial cells, astrocytes and pericytes, within the extracellular matrix of the brain and with the blood flow in the capillaries.

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While the blood-brain barrier ensuring the passage of oxygen, carbon dioxide and glucose it blocks the passage of compounds including drug molecules designed to treat human disease, as well as proteins and cells.

Danica Stanimirovic, Kristin Kemmerich,  Arsalan Haqqani, Graham Farrington, researchers from the Human Health Therapeutics Portfolio, National Research Council of Canada, Ottawa, Ontario, Canada and Biogen Idec Inc., Cambridge, Massachusetts, USA, found that increased brain penetration of therapeutic antibodies can be achieved by engineering bispecific antibodies in which one antibody binding specificity recognizes a blood-brain barrier receptor that undergoes receptor-mediated transcytosis from the circulatory compartment into brain parenchyma, and the second binding specificity recognizes a therapeutic target within the central nervous system.

Bispecific antibodies are unique in a sense that they combine two or more antigen-recognizing elements into a single construct, which allows them to bind to two or more targets.

Antibody fragments
These bispecific antibodies can be built using various antibody fragments as “building blocks,” including monomeric single-domain antibodies, the smallest antigen-binding fragments of immunoglobulins. The development of blood-brain barrier -crossing bispecific antibodies requires targeted antibody engineering to optimize multiple characteristics of ” blood-brain barrier carrier” and therapeutic arms, as well as other antibody properties impacting pharmacokinetics and effector function.

Bispecific antibodies
Over the years, several blood-brain barrier-crossing bispecific antibodies have been developed using transferrin receptor antibodies as blood-brain barrier carriers. However, the principal obstacle for capitalizing on this future promise of central nervous system -active antibodies remains the scarcity of known, characterized receptor-mediated transcytosis receptors which could be exploited for the development of blood-brain barrier carriers.

In Advances in Pharmacology; Pharmacology of the Blood Brain Barrier: Targeting CNS Disorders, volume 71, 2014, Stanimirovic  and her team review the recent advances and guiding principles for designing, engineering, and evaluating blood-brain barrier-crossing bispecific antibodies. The authors also discusses approaches to identify and characterize novel blood-brain barrier-crossing antibodies and receptor-mediated transcytosis receptors. [1]

In an unrelated study the researchers demonstrates that modular incorporation of the blood-brain barrier permeable single-domain antibody FC5 in bispecific antibodies or antibody-drug conjugates offers an avenue to develop pharmacologically active biotherapeutics for central nervous system indications. [2]