Engineering anti-amyloid antibodies with transferrin receptor targeting improves safety and brain biodistribution

Pizzo, M. E.; Plowey, E. D.; Khoury, N.; Kwan, W.; Abettan, J.; DeVos, S. L.; Discenza, C. B.; Earr, T.; Joy, D.; Lye-Barthel, M.; Roche, E.; Chan, D.; Dugas, J. C.; Gadkar, K.; Meisner, R.; Sebalusky, J.; Silva Amaral, A. C.; Becerra, I.; Chau, R.; Chow, J.; Clemens, A. J.; Dennis, M. S.; Duque, J.; Fusaro, L.; Getz, J. A.; Kariolis, M. S.; Kim, D. J.; Leung, A. W.-S.; Nguyen, H. N.; Thomsen, E. R.; Sanchez, P. E.; Shan, L.; Silverman, A. P.; Solanoy, H.; Tong, R.; Calvert, M. E. K.; Watts, R. J.; Thorne, R. G.; Weinreb, P. H.; Walsh, D. M.; Lewcock, J. W.; Bussiere, T.; Zuchero, Y. J. Y.

doi:10.1101/2024.07.26.604664

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bioRxiv · 10.1101/2024.07.26.604664

Engineering anti-amyloid antibodies with transferrin receptor targeting improves safety and brain biodistribution

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Abstract

Although the first generation of immunotherapies for Alzheimers disease (AD) are now clinically approved, amyloid-related imaging abnormalities (ARIA) remain a major safety problem for this class of drugs. Here, we report an antibody transport vehicle (ATV) targeting the transferrin receptor (TfR) for brain delivery of amyloid beta (A{beta}) antibodies that significantly reduced ARIA-like lesions and improved plaque target engagement in a mouse model of amyloid deposition. Asymmetrical Fc mutations (ATVcisLALA) allowed the molecule to selectively retain effector function only when bound to A{beta} while mitigating TfR-related hematology liabilities. Mice treated with ATVcisLALA:A{beta} exhibited broad brain parenchymal antibody distribution; in contrast, anti-A{beta} IgG was highly enriched at arterial perivascular spaces where vascular A{beta} localizes and likely plays a role in induction of ARIA. Importantly, ATVcisLALA: A{beta} almost completely eliminated ARIA-like lesions and vascular inflammation associated with anti-A{beta} treatment. Taken together, ATVcisLALA has the potential to significantly improve both safety and efficacy of A{beta} immunotherapy through enhanced biodistribution mediated by transport across the blood-brain barrier.

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Pizzo, M. E., Plowey, E. D., Khoury, N., Kwan, W., Abettan, J., DeVos, S. L., Discenza, C. B., Earr, T., Joy, D., Lye-Barthel, M., Roche, E., Chan, D., Dugas, J. C., Gadkar, K., Meisner, R., Sebalusky, J., Silva Amaral, A. C., Becerra, I., Chau, R., Chow, J., Clemens, A. J., Dennis, M. S., Duque, J., Fusaro, L., Getz, J. A., Kariolis, M. S., Kim, D. J., Leung, A. W.-S., Nguyen, H. N., Thomsen, E. R., Sanchez, P. E., Shan, L., Silverman, A. P., Solanoy, H., Tong, R., Calvert, M. E. K., Watts, R. J., Thorne, R. G., Weinreb, P. H., Walsh, D. M., Lewcock, J. W., Bussiere, T., Zuchero, Y. J. Y.. 2024-07-26. Engineering anti-amyloid antibodies with transferrin receptor targeting improves safety and brain biodistribution. https://doi.org/10.1101/2024.07.26.604664

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