PO.ET02.05 · 实验与分子治疗
利用完全Fc静默抗体平台实现治疗指数最大化
Maximizing therapeutic index using fully Fc-silent antibody platform
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
在过去二十年中，抗体-药物偶联物（ADC）在连接子和载荷化学的深入研究推动下，彻底改变了癌症治疗的临床格局。然而，毒性问题仍令人担忧，损害ADC剂量和给药频率的因素可能影响总体临床获益。我们通过在抗体Fc区引入特定突变，开发了Stealth-Body（SB），在不损害疗效并保持生产可扩展性的前提下，限制Fc-Fcγ受体相互作用。与LALA突变相比，SB Fc在双转基因小鼠（huFcRn和hualbumin）的血清研究中表现出改善的药代动力学（PK）参数，如血清半衰期，并完全丧失了对所有Fcγ受体以及C1q的结合能力。基于这些特性，我们正在开发含SB Fc的ADC，以实现选择性抗肿瘤疗效并限制与Fcγ受体的相互作用，从而减少脱靶毒性。将含WT Fc和SB Fc的抗体与MMAE偶联，并在体外和体内研究中测定疗效。目前，小鼠PK研究和非人灵长类动物的初步毒理学研究正在进行中。为确定SB Fc偶联物是否能够避免脱靶毒性，用含SB Fc的偶联物或WT Fc偶联物处理表达FcγR的癌细胞系。正如预期，与WT Fc偶联物相比，SB Fc偶联物在这些细胞系中未表现出脱靶细胞杀伤毒性。含SB Fc的偶联物在癌细胞系体外实验中维持了与含WT Fc偶联物相似的强效疗效，表明SB Fc中的突变未损害疗效。在细胞系来源异种移植（CDX）体内模型中，SB Fc偶联物在单次注射剂量下表现出强烈的肿瘤生长抑制（TGI），并在CDX模型中观察到相似的强效最低有效剂量（MED），确定为0.6 mg/kg。这些临床前数据证明了含SB Fc的ADC作为治疗多种癌症适应症的有前景潜力，并支持其用于临床开发。
查看英文原文 English abstract
Antibody drug conjugates (ADCs) have transformed the clinical landscape for the treatment of cancers over the last two decades spear-headed by intensive research of linker and payload chemistries. However, toxicities remain a concern where impairing dosage and administration frequency of the ADCs could impact overall clinical benefit. We developed Stealth-Body (SB) by introducing specific mutations in the Fc region of the antibody to limit Fc-Fcgamma receptor interactions without compromising efficacy and maintaining manufacturing scalability, when compared to LALA mutations, the SB Fc showed improved pharmacokinetic (PK) parameters such as half-life in serum studies in double transgenic mice (huFcRn and hualbumin) and complete loss of binding to all Fcgamma receptors as well as C1q. Based on these characteristics, we are developing a ADCs containing SB Fc for selective anti-tumor efficacy and limiting interaction with Fcgamma receptors to reduce off-target toxicities. Antibodies containing WT Fc and SB Fcs were conjugated with MMAE and efficacy was determined in in vitro and in vivo studies. Currently, PK studies in mice and preliminary toxicology studies in non-human primates are ongoing. To determine whether SB Fc conjugates were able to avoid off-target toxicities, cancer cell lines expressing FcgammaRs were treated with SB Fc containing conjugates or WT Fc conjugates. As expected, the SB Fc conjugates displayed no off-target cell killing toxicities in these cell lines compared to WT Fc conjugates. Conjugates containing the SB Fcs maintained potent efficacy in vitro in cancer cell lines similar WT Fc containing conjugates, indicating that efficacy was not compromised by the mutations in the SB Fc. In in vivo cell line derived xenograft (CDX) models, the SB Fc conjugates showed strong tumor growth inhibition (TGI) as single injection doses and similar potent minimum efficacious dose (MED) was observed in CDX models and determined to be 0.6 mg/kg. These preclinical data demonstrate the potential of SB Fc containing ADCs as promising for the treatment of various cancer indications and supports their use for clinical development.
利益披露 Disclosure
K. Chang, None.