Hollevoet Kevin, Thomas Debby, Compernolle Griet, Vermeire Giles, De Smidt Elien, De Vleeschauwer Stéphanie, Smith Trevor R F, Fisher Paul D, Dewilde Maarten, Geukens Nick, Declerck Paul
PharmAbs, The KU Leuven Antibody Center - University of Leuven, Leuven, Belgium.
Laboratory for Therapeutic and Diagnostic Antibodies, KU Leuven - University of Leuven, Leuven, Belgium.
Front Oncol. 2022 Oct 3;12:1017612. doi: 10.3389/fonc.2022.1017612. eCollection 2022.
DNA-encoded delivery and expression of antibody therapeutics presents an innovative alternative to conventional protein production and administration, including for cancer treatment. To support clinical translation, we evaluated this approach in 18 40-45 kg sheep, using a clinical-matched intramuscular electroporation (IM EP) and hyaluronidase-plasmid DNA (pDNA) coformulation setup. Two cohorts of eight sheep received either 1 or 4 mg pDNA encoding an ovine anti-cancer embryonic antigen (CEA) monoclonal antibody (mAb; OVAC). Results showed a dose-response with average maximum serum concentrations of respectively 0.3 and 0.7 µg/ml OVAC, 4-6 weeks after IM EP. OVAC was detected in all 16 sheep throughout the 6-week follow-up, and no anti-OVAC antibodies were observed. Another, more exploratory, cohort of two sheep received a 12 mg pOVAC dose. Both animals displayed a similar dose-dependent mAb increase and expression profile in the first two weeks. However, in one animal, an anti-OVAC antibody response led to loss of mAb detection four weeks after IM EP. In the other animal, no anti-drug antibodies were observed. Serum OVAC concentrations peaked at 4.9 µg/ml 6 weeks after IM EP, after which levels gradually decreased but remained detectable around 0.2 to 0.3 µg/ml throughout a 13-month follow-up. In conclusion, using a delivery protocol that is currently employed in clinical Phase 1 studies of DNA-based antibodies, we achieved robust and prolonged production of anti-cancer DNA-encoded antibody therapeutics in sheep. The learnings from this large-animal model regarding the impact of pDNA dose and host immune response on the expressed mAb pharmacokinetics can contribute to advancing clinical translation.
DNA编码的抗体疗法的递送和表达为传统蛋白质生产和给药提供了一种创新的替代方法，包括用于癌症治疗。为支持临床转化，我们在18只体重40 - 45千克的绵羊中评估了这种方法，采用了临床匹配的肌肉内电穿孔（IM EP）和透明质酸酶 - 质粒DNA（pDNA）共配制设置。两组八只绵羊分别接受了1毫克或4毫克编码羊抗癌胚抗原（CEA）单克隆抗体（mAb；OVAC）的pDNA。结果显示出剂量反应，IM EP后4 - 6周，OVAC的平均最大血清浓度分别为0.3和0.7微克/毫升。在为期6周的随访中，在所有16只绵羊中均检测到了OVAC，且未观察到抗OVAC抗体。另外一组两只绵羊进行了更具探索性的研究，接受了12毫克pOVAC剂量。两只动物在前两周均表现出类似的剂量依赖性mAb增加和表达谱。然而，在一只动物中，抗OVAC抗体反应导致IM EP后四周无法检测到mAb。在另一只动物中，未观察到抗药物抗体。IM EP后6周，血清OVAC浓度峰值达到4.9微克/毫升，此后水平逐渐下降，但在为期13个月的随访中一直保持在0.2至0.3微克/毫升左右可检测到。总之，使用目前在基于DNA的抗体的临床1期研究中采用的递送方案，我们在绵羊中实现了抗癌DNA编码抗体疗法的强劲且持久的生产。从这个大型动物模型中获得的关于pDNA剂量和宿主免疫反应对表达的mAb药代动力学影响的经验教训，有助于推进临床转化。
