HuCAL Antibody Combats Alzheimer’s Disease Marlies Sproll, PhD, CSO MorphoSys AG Planegg, Germany Drug Discovery & Development - October 13, 2010
Alzheimer’s disease (AD) affects 5.3 million people and is the seventh leading cause of death and the most common type of dementia in the United States.1 Alzheimer’s is an incurable, progressive disease, and the treatments currently available only serve to alleviate its symptoms. Thus, AD represents the largest unmet need in neurology. Early diagnosis and therapeutic strategies that could delay the onset and progression of this debilitating disease would be considered a success.
Pathological hallmarks of AD are the deposits of extracellular amyloid-beta (Aß) plaques, intraneuronal tangles—composed of hyperphosphorylated tau—and cerebral neuronal loss. Therefore, strategies to develop drug candidates with potential disease-modifying effects tend to focus on inhibiting Aß production and aggregation or they aim to increase the Aß clearance from the brain. These strategies include secretase modulators, anti-tau drugs to reduce the phosphorylation of tau by inhibiting specific kinases, and drugs that directly target Aß-plaques.2
A promising approach for the treatment of AD is immunotherapy that targets Aß. Strategies of drugs currently in development include vaccination to activate the body’s own immune system and therapeutic antibodies. Much was learned from the first immunotherapy clinical trial with an active anti-Aß vaccination (AN1792) in patients with mild-to-moderate AD, where 6% of treated patients developed meningoencephalitis and the trial was halted.3 Currently, over 30 immunotherapeutic drugs are in development, and roughly half are therapeutic antibodies.
A major challenge for today’s AD drug candidates, particularly for therapeutic antibodies, is the blood-brain barrier. Once considered impermeable for large molecules such as immunoglobulins, recent evidence has shown that larger molecules are in fact able to pass this barrier, but it is still difficult to develop drugs that can do so effectively.
Therapeutic antibodies could be a valuable option for treating AD, but any potential antibody drugs will have to satisfy the following criteria: the antibodies must be able to cross the blood-brain barrier, demonstrate high target affinity, and dissolve the Aß plaques in vivo.
A collaboration between MorphoSys and Roche made use of HuCAL (Human Combinatorial Antibody Library) for isolating a specific human antibody that could target and dissolve Aß plaques. HuCAL, MorphoSys’s proprietary antibody library, is a technology designed for the in vitro generation of fully human antibodies; the genetic design of the HuCAL system allows the systematic engineering of the properties of any antibody isolated from the library.
Preclinical tests have demonstrated the high specificity and affinity of this MorphoSys/Roche HuCAL antibody, gantenerumab, and its ability to dissolve accumulated Aß plaques in vitro. Epitope mapping revealed the involvement of the N-terminal and central parts of the Aß antigen in binding gantenerumab, suggesting recognition of a conformational epitope exposed on Aß fibrils. Additional experiments proved that the antibody was highly specific to human Aß plaques in unfixed human brain tissue derived from AD patients. Furthermore, it was shown in human APP-transgenic animal models that gantenerumab is able to cross the blood-brain barrier and bind to both dense and diffuse Aß-plaques. Peripheral Aß levels were not increased after administration of the human mAb to the transgenic mice, suggesting that clearance of peripheral Aß was not affected.4
Gantenerumab was originally isolated and optimized at MorphoSys. The project then moved to MorphoSys’s pharmaceutical partner Roche, where gantenerumab is currently in Phase 1 clinical trials; it is expected that Phase 2 studies will start recruiting patients in the first half of 2011.
References 1. Alzheimer’s Facts and Figures. Alzheimer’s Association. Available at http://www.alz.org. Accessed on September 27, 2010 2. Blennow K, de Leon MJ, Zetterberg H. Alzheimer’s disease. Lancet. 2006; 29;368(9533):387. 3. Hawkes CA, McLaurin J. Expert Rev Neurother. 2007; 7(11):1535. 4. Literature/presentation of preclinical data: Bohrmann B. et al, ICAD 2010, Poster #P3-420
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