Niazi Sarfaraz K
College of Pharmacy, University of Illinois, Chicago, IL 60612, USA.
Biomedicines. 2024 Dec 22;12(12):2918. doi: 10.3390/biomedicines12122918.
Monoclonal antibodies approved by the FDA, lecanemab, donanemab, and aducanumab, are failing to meet the expected efficacy to treat early Alzheimer's disease, and aducanumab has been recalled. : Recently, it was reported that the clinical trials of these antibodies may have violated patient's rights and subjected them to high, likely lethal risk. The challenge with developing antibodies to treat neurological disorders is their poor blood-brain barrier (BBB) penetration if the antibody must enter the brain, resulting in almost negligible brain bioavailability, requiring high dosing that can be toxic. : The reported efficacy of these drugs should also be reviewed, considering the placebo effects, since all antibodies have shown severe side effects that are not prevented by the placebo responses. In this critical and urgent advice to the FDA, I am suggesting a guideline amendment to all clinical trials requiring proof of sufficient brain bioavailability at the site of action, where it is known. : For antibodies to cross the blood-brain barrier, there are proven options such as conjugating with transferrin protein, making clinical trials in its absence more questionable.
美国食品药品监督管理局（FDA）批准的单克隆抗体药物，如仑卡奈单抗、多奈单抗和阿杜卡单抗，在治疗早期阿尔茨海默病方面未能达到预期疗效，阿杜卡单抗已被召回。最近有报道称，这些抗体的临床试验可能侵犯了患者权利，并使他们面临高风险，甚至可能是致命风险。如果抗体必须进入大脑，那么开发用于治疗神经系统疾病的抗体所面临的挑战在于其血脑屏障（BBB）穿透性差，导致脑内生物利用度几乎可以忽略不计，这就需要高剂量给药，而高剂量可能有毒性。鉴于所有抗体都显示出严重的副作用，且安慰剂反应无法预防这些副作用，因此在考虑安慰剂效应的情况下，也应对这些药物已报道的疗效进行审查。在这份给FDA的关键且紧急的建议中，我提议对所有临床试验的指导原则进行修订，要求在已知作用部位证明有足够的脑内生物利用度。对于抗体穿过血脑屏障，有一些已证实的方法，比如与转铁蛋白结合，因此在缺乏这些方法的情况下进行临床试验更值得怀疑。
