Conquering the Barriers: Are Antibody Therapeutics Feasible for CNS Indications?

Danica Stanimirovic; Kristin Kemmerich


Future Neurology. 2015;10(2):67-70. 

In This Article

Lagging Behind: Barriers to CNS Drug Development

The major hurdles on the development path of CNS therapeutics include an inherent complexity of the CNS, highly restricted drug access to CNS targets by the blood–brain barrier (BBB), paucity of translational preclinical disease models, safety risks, and lack of clinical biomarkers to aid in patient selection and early assessment of efficacy in clinical trials. Drug development for CNS is therefore highly complex and risky – more expensive and lengthy than for any other indication. The CNS drugs have one of the highest pipeline attrition rates and longest development times (114 months); clinical trial failures tend to occur later in the clinical development, making the cost of developing a CNS drug among the highest of any therapeutic indication.[1,2]

Antibody drugs have become an increasingly significant component of the therapeutic landscape, achieving higher approval rates compared with nonbiologics (synthetic molecules). Antibodies exhibit very high specificity and selectivity, reducing risks of 'off-target' toxicity typical for synthetic molecules and enabling 'personalized' treatments.[3] Driven by clinical and commercial successes of 'the first wave' of therapeutic antibodies (e.g., anti-HER2 Trastuzumab in breast cancer and anti-TNFα Humira in rheumatoid arthritis), the antibody pipelines for oncology and inflammatory diseases have swelled to over 130 candidates in Phase 1 or beyond.[1–3] Regrettably, CNS indications have been left behind in this biologics 'revolution,' missing sorely the opportunity to benefit from novel, precise, disease-modifying antibody therapeutics. The overwhelming majority of all CNS therapeutics remain small molecules and there are currently no approved therapeutic antibodies for nonimmunological neurological diseases.

The cause for this 'state of affairs' has not been lack of trying. For example, immunotherapy for Alzheimer's disease (AD) has generated intense interest and led to the development of therapeutic antibodies against amyloid β (Aβ) and tau proteins.[4] Antibodies generated against various epitopes of Aβ proceeded to human trials based on the belief that the elimination of brain amyloid deposits would be accelerated by 'mopping up' and removing circulating amyloid – without much consideration given as to whether and which levels of antibodies are required in the brain parenchyma to 'engage' and remove central Aβ deposits. Among active and passive anti-Aβ immunotherapies for AD, bapineuzumab and solanezumab, two humanized monoclonal antibodies, failed to show significant clinical benefits in mild-to-moderate AD patients in large Phase III clinical trials.[5] It is now believed that predominantly peripherally restricted actions of Aβ antibodies are not sufficient and that their delivery across the BBB is required to produce a central therapeutic effect. Indeed, Aβ-binding antibody fragments delivered centrally were highly effective in preventing Aβ-deposition in transgenic models.[6] These expensive clinical failures of AD immunotherapy were instrumental in recognizing the need to integrate the development of BBB-delivery technologies into preclinical and clinical development of biotherapeutics for CNS indications.