Neurodegeneration Labs, Department of Neuroscience, Genentech Inc., South San Francisco, CA 94080, USA.
Sci Transl Med. 2011 May 25;3(84):84ra44. doi: 10.1126/scitranslmed.3002230.
Monoclonal antibodies have therapeutic potential for treating diseases of the central nervous system, but their accumulation in the brain is limited by the blood-brain barrier (BBB). Here, we show that reducing the affinity of an antibody for the transferrin receptor (TfR) enhances receptor-mediated transcytosis of the anti-TfR antibody across the BBB into the mouse brain where it reaches therapeutically relevant concentrations. Anti-TfR antibodies that bind with high affinity to TfR remain associated with the BBB, whereas lower-affinity anti-TfR antibody variants are released from the BBB into the brain and show a broad distribution 24 hours after dosing. We designed a bispecific antibody that binds with low affinity to TfR and with high affinity to the enzyme β-secretase (BACE1), which processes amyloid precursor protein into amyloid-β (Aβ) peptides including those associated with Alzheimer's disease. Compared to monospecific anti-BACE1 antibody, the bispecific antibody accumulated in the mouse brain and led to a greater reduction in brain Aβ after a single systemic dose. TfR-facilitated transcytosis of this bispecific antibody across the BBB may enhance its potency as an anti-BACE1 therapy for treating Alzheimer's disease.
单克隆抗体在治疗中枢神经系统疾病方面具有治疗潜力，但由于血脑屏障 (BBB) 的存在，其在大脑中的积累受到限制。在这里，我们表明，降低抗体与转铁蛋白受体 (TfR) 的亲和力可以增强受体介导的抗 TfR 抗体穿过 BBB 进入小鼠大脑的转胞吞作用，从而达到治疗相关浓度。与 TfR 具有高亲和力结合的抗 TfR 抗体仍与 BBB 相关联，而亲和力较低的抗 TfR 抗体变体则从 BBB 释放到大脑中，并在给药后 24 小时内显示出广泛的分布。我们设计了一种双特异性抗体，它与 TfR 具有低亲和力，与酶β-分泌酶 (BACE1) 具有高亲和力，BACE1 将淀粉样前体蛋白加工成包括与阿尔茨海默病相关的淀粉样-β (Aβ) 肽。与单特异性抗 BACE1 抗体相比，双特异性抗体在小鼠大脑中的积累更多，并在单次全身给药后导致大脑 Aβ 减少更多。这种双特异性抗体通过 TfR 促进穿过 BBB 的转胞吞作用可能会增强其作为治疗阿尔茨海默病的抗 BACE1 疗法的效力。
