Optimizing the interaction between antibody (mAb)-based therapeutics and immune effector functions (EFs) offers opportunities to improve the therapeutic window of these molecules. However, the role of EFs in antibody-drug conjugate (ADC) efficacy and toxicity remains unknown, with limited studies that have investigated how modulation of EF affects the pharmacology of ADCs. This study aimed to evaluate the effect of EF modulation on ADC efficacy using trastuzumab-vc-MMAE as a model ADC. A series of ADCs with enhanced or eradicated EF were synthesized through Fc engineering of the antibody. Cell-based assays confirmed that the alteration of EFs in ADCs did not change their in vitro potency, and the conjugation of vc-MMAE did not alter the trends in EFs modulation. Pharmacokinetic/pharmacodynamic (PK/PD) studies of Fc engineered ADCs were conducted in a syngeneic mouse system. The enhancement of EFs led to lower systemic exposure, faster clearance, and potentially enhanced tissue distribution and accumulation of ADCs. ADCs with enhanced EFs demonstrated improved efficacy in the syngeneic mouse tumor model, which was quantitatively confirmed by PK/PD modeling. The model indicated that EF enhancement was synergistic for ADC efficacy, whereas the complete removal of EF was less than additive. Our study suggests that developing ADCs with enhanced EF may improve the therapeutic effectiveness of ADCs, although the effect of this modification on ADC safety and extrapolation of our findings to other ADCs necessitates further investigation.

Hsuan-Ping Chang

Shufang Liu

Dhaval K. Shah

The AAPS Journal

AAPS 杂志是美国药物科学家协会 (AAPS) 的官方期刊，发表了影响人类和兽医治疗的药物科学各个领域的新颖而重要的发现，包括：· 药物设计和发现· 制药生物技术· 生物制药、制剂, 和药物递送· 代谢和运输· 药代动力学、药效学和药效学· 转化研究· 临床评估和治疗结果· 监管科学我们邀请以下文章类型提交：· 原创研究文章· 评论和小型评论· 白皮书、评论, 和社论· 会议报告· 简要/技术报告和快速通信· 监管说明· 教程· 药物科学协议此外，AAPS 期刊还发布由客座编辑组织的主题，重点关注我们领域当前感兴趣的特定领域.

AAPS Journal is the official journal of the American Association of Pharmaceutical Scientists (AAPS), publishing novel and significant findings across various fields of pharmaceutical science that impact human and veterinary therapeutics. The main topics include: drug design and discovery, pharmaceutical biotechnology, biopharmaceuticals, formulation and drug delivery, metabolism and transport, pharmacokinetics, pharmacodynamics, translational research, clinical evaluation and therapeutic outcomes, and regulatory science. We invite submissions of the following article types: original research articles, reviews and mini-reviews, white papers, commentaries and editorials, conference reports, brief/technical reports and rapid communications, regulatory guidelines, tutorials, and pharmaceutical science protocols. Additionally, AAPS Journal publishes themed issues organized by guest editors, focusing on specific areas of current interest in our field.

AAPS Journal 是美国药物科学家协会 (AAPS) 的官方期刊，发表影响人类和兽医治疗的药物科学各个领域的新颖而重要的发现。主要涵盖以下主题：药物设计与发现、制药生物技术、生物制药、制剂与药物递送、代谢与运输、药代动力学、药效学、转化研究、临床评估与治疗结果以及监管科学。我们欢迎以下类型的文章提交：原创研究文章、评论与小型评论、白皮书、评论与社论、会议报告、简要/技术报告与快速通信、监管说明、教程及药物科学协议。此外，AAPS Journal 还发布由客座编辑组织的主题，重点关注我们领域当前感兴趣的特定领域。

Category	Quartile
医学	3
医学, 药学	3

PK/PD Evaluation of Antibody–Drug Conjugates with Enhanced Immune Effector Functions

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Journal Info

Category	Quartile
PHARMACOLOGY & PHARMACY	1