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Nonclinical immunogenicity risk assessment for knobs-into-holes bispecific IgG1 antibodies. 旋钮-孔双特异性 IgG1 抗体的非临床免疫原性风险评估。
IF 5.3 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-01-01 Epub Date: 2024-06-06 DOI: 10.1080/19420862.2024.2362789
Wen-Ting K Tsai, Yinyin Li, Zhaojun Yin, Peter Tran, Qui Phung, Zhenru Zhou, Kun Peng, Dan Qin, Sien Tam, Christoph Spiess, Jochen Brumm, Manda Wong, Zhengmao Ye, Patrick Wu, Sivan Cohen, Paul J Carter

Bispecific antibodies, including bispecific IgG, are emerging as an important new class of antibody therapeutics. As a result, we, as well as others, have developed engineering strategies designed to facilitate the efficient production of bispecific IgG for clinical development. For example, we have extensively used knobs-into-holes (KIH) mutations to facilitate the heterodimerization of antibody heavy chains and more recently Fab mutations to promote cognate heavy/light chain pairing for efficient in vivo assembly of bispecific IgG in single host cells. A panel of related monospecific and bispecific IgG1 antibodies was constructed and assessed for immunogenicity risk by comparison with benchmark antibodies with known low (Avastin and Herceptin) or high (bococizumab and ATR-107) clinical incidence of anti-drug antibodies. Assay methods used include dendritic cell internalization, T cell proliferation, and T cell epitope identification by in silico prediction and MHC-associated peptide proteomics. Data from each method were considered independently and then together for an overall integrated immunogenicity risk assessment. In toto, these data suggest that the KIH mutations and in vitro assembly of half antibodies do not represent a major risk for immunogenicity of bispecific IgG1, nor do the Fab mutations used for efficient in vivo assembly of bispecifics in single host cells. Comparable or slightly higher immunogenicity risk assessment data were obtained for research-grade preparations of trastuzumab and bevacizumab versus Herceptin and Avastin, respectively. These data provide experimental support for the common practice of using research-grade preparations of IgG1 as surrogates for immunogenicity risk assessment of their corresponding pharmaceutical counterparts.

包括双特异性 IgG 在内的双特异性抗体正在成为一类重要的新型抗体疗法。因此,我们和其他公司一起开发了工程策略,旨在促进双特异性 IgG 的高效生产,以用于临床开发。例如,我们广泛使用 "knobs-into-holes"(KIH)突变来促进抗体重链的异源二聚化,最近又使用 Fab 突变来促进同源重链/轻链配对,从而在单个宿主细胞中高效地在体内组装双特异性 IgG。我们构建了一个相关的单特异性和双特异性 IgG1 抗体面板,并通过与已知抗药抗体临床发生率低(阿瓦斯汀和赫赛汀)或高(博西珠单抗和 ATR-107)的基准抗体进行比较,评估免疫原性风险。使用的检测方法包括树突状细胞内化、T 细胞增殖、通过硅预测和 MHC 相关肽蛋白质组学鉴定 T 细胞表位。每种方法的数据都是独立考虑的,然后一起进行整体综合免疫原性风险评估。总之,这些数据表明,KIH 突变和体外组装半抗并不构成双特异性 IgG1 免疫原性的主要风险,用于在体内单宿主细胞中高效组装双特异性抗体的 Fab 突变也不构成主要风险。研究级制剂曲妥珠单抗和贝伐珠单抗的免疫原性风险评估数据分别与赫赛汀和阿瓦斯汀相当或略高。这些数据为使用研究级 IgG1 制剂作为替代物对相应药物进行免疫原性风险评估的普遍做法提供了实验支持。
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引用次数: 0
Engineering a tumor-selective prodrug T-cell engager bispecific antibody for safer immunotherapy. 为更安全的免疫疗法设计肿瘤选择性原药 T 细胞吸引双特异性抗体。
IF 5.6 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-01-01 Epub Date: 2024-07-04 DOI: 10.1080/19420862.2024.2373325
Amelia C McCue, Stephen J Demarest, Karen J Froning, Michael J Hickey, Stephen Antonysamy, Brian Kuhlman

T-cell engaging (TCE) bispecific antibodies are potent drugs that trigger the immune system to eliminate cancer cells, but administration can be accompanied by toxic side effects that limit dosing. TCEs function by binding to cell surface receptors on T cells, frequently CD3, with one arm of the bispecific antibody while the other arm binds to cell surface antigens on cancer cells. On-target, off-tumor toxicity can arise when the target antigen is also present on healthy cells. The toxicity of TCEs may be ameliorated through the use of pro-drug forms of the TCE, which are not fully functional until recruited to the tumor microenvironment. This can be accomplished by masking the anti-CD3 arm of the TCE with an autoinhibitory motif that is released by tumor-enriched proteases. Here, we solve the crystal structure of the antigen-binding fragment of a novel anti-CD3 antibody, E10, in complex with its epitope from CD3 and use this information to engineer a masked form of the antibody that can activate by the tumor-enriched protease matrix metalloproteinase 2 (MMP-2). We demonstrate with binding experiments and in vitro T-cell activation and killing assays that our designed prodrug TCE is capable of tumor-selective T-cell activity that is dependent upon MMP-2. Furthermore, we demonstrate that a similar masking strategy can be used to create a pro-drug form of the frequently used anti-CD3 antibody SP34. This study showcases an approach to developing immune-modulating therapeutics that prioritizes safety and has the potential to advance cancer immunotherapy treatment strategies.

T细胞参与(TCE)双特异性抗体是一种强效药物,可激发免疫系统消灭癌细胞,但用药可能会产生毒副作用,从而限制剂量。双特异性抗体的一个臂与 T 细胞的细胞表面受体(通常是 CD3)结合,而另一个臂则与癌细胞的细胞表面抗原结合。当目标抗原也存在于健康细胞上时,就会产生靶上、瘤外毒性。可通过使用原药形式的 TCE 来减轻 TCE 的毒性,原药形式的 TCE 在被招募到肿瘤微环境中之前并不完全起作用。这可以通过用肿瘤富集蛋白酶释放的自抑制基团掩盖 TCE 的抗 CD3 臂来实现。在这里,我们解析了一种新型抗 CD3 抗体 E10 的抗原结合片段与 CD3 表位复合的晶体结构,并利用这一信息设计了一种可被肿瘤富集蛋白酶基质金属蛋白酶 2 (MMP-2) 激活的抗体屏蔽形式。我们通过结合实验和体外 T 细胞活化与杀伤试验证明,我们设计的原药 TCE 能够依赖 MMP-2 发挥肿瘤选择性 T 细胞活性。此外,我们还证明了类似的掩蔽策略可用于制造常用的抗 CD3 抗体 SP34 的原药形式。这项研究展示了一种优先考虑安全性的免疫调节疗法的开发方法,有望推动癌症免疫疗法治疗策略的发展。
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引用次数: 0
FcRn-enhancing mutations lead to increased and prolonged levels of the HIV CCR5-blocking monoclonal antibody leronlimab in the fetuses and newborns of pregnant rhesus macaques. FcRn增强突变导致怀孕猕猴的胎儿和新生儿体内艾滋病毒CCR5阻断单克隆抗体eronlimab的水平升高且持续时间延长。
IF 5.6 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-01-01 Epub Date: 2024-09-26 DOI: 10.1080/19420862.2024.2406788
Joanna Zikos, Gabriela M Webb, Helen L Wu, Jason S Reed, Jennifer Watanabe, Jodie L Usachenko, Ala M Shaqra, Celia A Schiffer, Koen K A Van Rompay, Jonah B Sacha, Diogo M Magnani

Prenatal administration of monoclonal antibodies (mAbs) is a strategy that could be exploited to prevent viral infections during pregnancy and early life. To reach protective levels in fetuses, mAbs must be transported across the placenta, a selective barrier that actively and specifically promotes the transfer of antibodies (Abs) into the fetus through the neonatal Fc receptor (FcRn). Because FcRn also regulates Ab half-life, Fc mutations like the M428L/N434S, commonly known as LS mutations, and others have been developed to enhance binding affinity to FcRn and improve drug pharmacokinetics. We hypothesized that these FcRn-enhancing mutations could similarly affect the delivery of therapeutic Abs to the fetus. To test this hypothesis, we measured the transplacental transfer of leronlimab, an anti-CCR5 mAb, in clinical development for preventing HIV infections, using pregnant rhesus macaques to model in utero mAb transfer. We also generated a stabilized and FcRn-enhanced form of leronlimab, termed leronlimab-PLS. Leronlimab-PLS maintained higher levels within the maternal compartment while also reaching higher mAb levels in the fetus and newborn circulation. Further, a single dose of leronlimab-PLS led to complete CCR5 receptor occupancy in mothers and newborns for almost a month after birth. These findings support the optimization of FcRn interactions in mAb therapies designed for administration during pregnancy.

产前服用单克隆抗体(mAbs)是一种可用于预防孕期和生命早期病毒感染的策略。胎盘是一道选择性屏障,可通过新生儿 Fc 受体(FcRn)主动、特异地促进抗体(Abs)转移到胎儿体内,从而使胎儿体内的 mAbs 达到保护水平。由于 FcRn 还能调节抗体的半衰期,因此人们开发了 M428L/N434S 等 Fc 突变(通常称为 LS 突变),以增强与 FcRn 的结合亲和力,改善药物的药代动力学。我们假设,这些增强 FcRn 的突变同样会影响治疗药物 Abs 向胎儿的输送。为了验证这一假设,我们使用怀孕的恒河猴来模拟 mAb 在子宫内的转移,测量了用于预防 HIV 感染的临床开发中的抗 CCR5 mAb leronlimab 的胎盘转移情况。我们还生成了一种稳定的 FcRn 增强型来龙利单抗,称为来龙利单抗-PLS。Leronlimab-PLS在母体内保持了较高的水平,同时在胎儿和新生儿循环中也达到了较高的mAb水平。此外,单剂量的leronlimab-PLS可使母体和新生儿在出生后近一个月内完全占据CCR5受体。这些发现为优化孕期用药 mAb 疗法中的 FcRn 相互作用提供了支持。
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引用次数: 0
Rapid depletion of "catch-and-release" anti-ASGR1 antibody in vivo. 体内 "捕获-释放 "抗 ASGR1 抗体的快速消耗。
IF 5.6 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-01-01 Epub Date: 2024-07-25 DOI: 10.1080/19420862.2024.2383013
Siva Charan Devanaboyina, Peng Li, Edward L LaGory, Carrie Poon-Andersen, Kevin D Cook, Marcus Soto, Zhe Wang, Khue Dang, Craig Uyeda, Ryan B Case, Veena A Thomas, Ronya Primack, Manuel Ponce, Mei Di, Brian Ouyang, Joelle Kaner, Sheung Kwan Lam, Mina Mostafavi

Targeting antigens with antibodies exhibiting pH/Ca2+-dependent binding against an antigen is an attractive strategy to mitigate target-mediated disposition and antigen buffering. Studies have reported improved serum exposure of antibodies exhibiting pH/Ca2+-binding against membrane-bound receptors. Asialoglycoprotein receptor 1 (ASGR1) is a membrane-bound receptor primarily localized in hepatocytes. With a high expression level of approximately one million receptors per cell, high turnover, and rapid recycling, targeting this receptor with a conventional antibody is a challenge. In this study, we identified an antibody exhibiting pH/Ca2+-dependent binding to ASGR1 and generated antibody variants with increased binding to neonatal crystallizable fragment receptor (FcRn). Serum exposures of the generated anti-ASGR1 antibodies were analyzed in transgenic mice expressing human FcRn. Contrary to published reports of increased serum exposure of pH/Ca2+-dependent antibodies, the pH/Ca2+-dependent anti-ASGR1 antibody had rapid serum clearance in comparison to a conventional anti-ASGR1 antibody. We conducted sub-cellular trafficking studies of the anti-ASGR1 antibodies along with receptor quantification analysis for mechanistic understanding of the rapid serum clearance of pH/Ca2+-dependent anti-ASGR1 antibody. The findings from our study provide valuable insights in identifying the antigens, especially membrane bound, that may benefit from targeting with pH/Ca2+-dependent antibodies to obtain increased serum exposure.

用表现出 pH/Ca2+ 依赖性结合抗原的抗体来靶向抗原是一种有吸引力的策略,可减轻靶向介导的处置和抗原缓冲。有研究报告称,针对膜结合受体的 pH/Ca2+ 结合抗体可改善血清暴露。Asialoglycoprotein receptor 1(ASGR1)是一种膜结合受体,主要定位于肝细胞。由于每个细胞中约有一百万个受体的高表达水平、高周转和快速循环,用常规抗体靶向该受体是一项挑战。在这项研究中,我们发现了一种能与 ASGR1 发生 pH/Ca2+ 依赖性结合的抗体,并生成了能增加与新生儿可结晶片段受体(FcRn)结合的抗体变体。我们在表达人类 FcRn 的转基因小鼠体内分析了所生成的抗 ASGR1 抗体的血清暴露情况。与pH/Ca2+依赖性抗体血清暴露增加的公开报道相反,pH/Ca2+依赖性抗ASGR1抗体与传统的抗ASGR1抗体相比血清清除迅速。我们对抗ASGR1抗体进行了亚细胞迁移研究,并进行了受体定量分析,以从机理上理解pH/Ca2+依赖性抗ASGR1抗体的快速血清清除。我们的研究结果为确定抗原(尤其是与膜结合的抗原)提供了有价值的见解,这些抗原可能受益于pH/Ca2+依赖性抗体的靶向作用,以获得更多的血清暴露。
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引用次数: 0
GB18-06, a nanobody targeting GDF15, effectively alleviates weight loss and restores physical function in cachexia models. GB18-06是一种靶向GDF15的纳米抗体,它能有效减轻恶病质模型的体重减轻并恢复其身体功能。
IF 5.6 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-01-01 Epub Date: 2024-10-14 DOI: 10.1080/19420862.2024.2416453
Yu Huang, Jinyong Wang, Xiling Wei, Hui Zhang, Wei Shang, Xiangling Zhang, Lanjiao Zhai, Xi Chen, Huiming Li, Suofu Qin

Cachexia is a complicated metabolic syndrome mainly associated with cancers, characterized by extreme weight loss and muscle wasting. It is a debilitating condition that negatively affects prognosis and survival. However, there is currently no effective pharmacological intervention that can reverse body weight loss and improve physical performance in patients with cachexia. Growth differentiation factor 15 (GDF15) can suppress appetite and regulate energy balance through binding to glial cell-derived neurotrophic factor receptor alpha-like (GFRAL). In order to develop a novel, effective treatment for cachexia, we generated a GDF15-targeting VHH nanobody, GB18-06, that was able to bind GDF15 with high affinity. In vitro, GB18-06 potently inhibited the GDF15-GFRAL signaling pathway, leading to a reduction of downstream ERK and AKT phosphorylation levels; in vivo, GB18-06 alleviated weight loss (>20%) in cancer and chemotherapy-induced cachexia models in mice. Compared with the control (phosphate-buffered saline) group, the ambulatory activity of mice in the GB18-06-treated group also increased 77%. Furthermore, GB18-06 exhibited desirable pharmacokinetic properties and an excellent developability profile. Our study has demonstrated a means of developing targeted treatment for cachexia with high efficacy, potentially leading to improved clinical outcomes and quality of life for patients with cachexia.

恶病质是一种复杂的代谢综合征,主要与癌症有关,其特点是体重极度下降和肌肉萎缩。它使人衰弱,对预后和存活产生负面影响。然而,目前还没有有效的药物干预措施可以逆转恶病质患者的体重减轻并改善其体能表现。生长分化因子15(GDF15)可通过与胶质细胞源性神经营养因子α样受体(GFRAL)结合来抑制食欲和调节能量平衡。为了开发一种新型、有效的恶病质治疗方法,我们生成了一种能与 GDF15 高亲和力结合的 GDF15 靶向 VHH 纳米抗体 GB18-06。在体外,GB18-06能有效抑制GDF15-GFRAL信号通路,导致下游ERK和AKT磷酸化水平降低;在体内,GB18-06能减轻癌症和化疗诱导的小鼠恶病质模型的体重下降(>20%)。与对照组(磷酸盐缓冲盐水)相比,GB18-06 治疗组小鼠的活动能力也提高了 77%。此外,GB18-06 还具有理想的药代动力学特性和出色的可开发性。我们的研究证明了一种开发高效恶病质靶向治疗的方法,有可能改善恶病质患者的临床疗效和生活质量。
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引用次数: 0
Residue-resolved insights into the stabilization of therapeutic proteins by excipients: A case study of two monoclonal antibodies with arginine and glutamate. 通过残留解析深入了解辅料对治疗用蛋白质的稳定作用:精氨酸和谷氨酸两种单克隆抗体的案例研究。
IF 5.6 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-01-01 Epub Date: 2024-11-14 DOI: 10.1080/19420862.2024.2427771
Tobias M Prass, Patrick Garidel, Lars V Schäfer, Michaela Blech

Protein formulation development relies on the selection of excipients that inhibit protein-protein interactions preventing aggregation. Empirical strategies involve screening many excipient and buffer combinations by physicochemical characterization using forced degradation or temperature-induced stress, mostly under accelerated conditions. Such methods do not readily provide information on the inter- and intramolecular interactions responsible for the effects of excipients. Here, we describe a combined experimental and computational approach for investigating the effect of protein-excipient interactions on formulation stability, which allows the identification of preferential interaction sites and thus can aid in the selection of excipients to be experimentally screened. Model systems composed of two marketed therapeutic IgG1 monoclonal antibodies with identical Fc domain sequences, trastuzumab and omalizumab, were investigated with commonly used excipients arginine, glutamate, and equimolar arginine/glutamate mixtures. Protein-excipient interactions were studied using all-atom molecular dynamics (MD) simulations, which show accumulation of the excipients at specific antibody regions. Preferential excipient-interaction sites were particularly found for charged and aromatic residues and in the complementary-determining regions, with more pronounced arginine contacts for omalizumab than trastuzumab. These computational findings are in line with the more pronounced stabilizing effects of arginine observed in the long-term storage stability study. Furthermore, the aggregation and solubility propensity predicted by commonly used in silico tools do not align with the preferential excipient-interaction sites identified by the MD simulations, suggesting that different physicochemical mechanisms are at play.

蛋白质制剂的开发有赖于选择能抑制蛋白质与蛋白质之间相互作用、防止聚集的辅料。经验策略包括利用强制降解或温度诱导应力(大多在加速条件下)进行理化表征,筛选多种辅料和缓冲剂组合。这些方法无法轻易提供有关辅料作用的分子间和分子内相互作用的信息。在此,我们介绍一种实验与计算相结合的方法,用于研究蛋白质与辅料之间的相互作用对制剂稳定性的影响,这种方法可以确定优先相互作用位点,从而有助于选择辅料进行实验筛选。研究了由两种具有相同 Fc 结构域序列的上市治疗用 IgG1 单克隆抗体(曲妥珠单抗和奥马珠单抗)组成的模型系统与常用辅料精氨酸、谷氨酸和等摩尔精氨酸/谷氨酸混合物的相互作用。使用全原子分子动力学(MD)模拟研究了蛋白质与辅料之间的相互作用,结果显示辅料在特定抗体区域聚集。在带电残基和芳香残基以及互补决定区发现了优先的辅料相互作用位点,奥马珠单抗的精氨酸接触比曲妥珠单抗更明显。这些计算发现与长期储存稳定性研究中观察到的精氨酸更明显的稳定作用相一致。此外,常用硅学工具预测的聚集和溶解倾向与 MD 模拟确定的优先赋形剂相互作用位点并不一致,这表明有不同的物理化学机制在起作用。
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引用次数: 0
Seq2scFv: a toolkit for the comprehensive analysis of display libraries from long-read sequencing platforms. Seq2scFv:用于综合分析长读数测序平台显示文库的工具包。
IF 5.6 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-01-01 Epub Date: 2024-10-08 DOI: 10.1080/19420862.2024.2408344
Marianne Bachmann Salvy, Luca Santuari, Emanuel Schmid-Siegert, Nikolaos Lykoskoufis, Ioannis Xenarios, Bulak Arpat

Antibodies have emerged as the leading class of biotherapeutics, yet traditional screening methods face significant time and resource challenges in identifying lead candidates. Integrating high-throughput sequencing with computational approaches marks a pivotal advancement in antibody discovery, expanding the antibody space to explore. In this context, a major breakthrough has been the full-length sequencing of single-chain variable fragments (scFvs) used in in vitro display libraries. However, few tools address the task of annotating the paired heavy and light chain variable domains (VH and VL), which is the primary advantage of full-scFv sequencing. To address this methodological gap, we introduce Seq2scFv, a novel open-source toolkit designed for analyzing in vitro display libraries from long-read sequencing platforms. Seq2scFv facilitates the identification and thorough characterization of V(D)J recombination in both VH and VL regions. In addition to providing annotated scFvs, translated sequences and numbered chains, Seq2scFv enables linker inference and characterization, sequence encoding with unique identifiers and quantification of identical sequences across selection rounds, thereby simplifying enrichment identification. With its versatile and standalone functionality, we anticipate that the implementation of Seq2scFv tools in antibody discovery pipelines will efficiently expedite the full characterization of display libraries and potentially facilitate the identification of high-affinity antibody candidates.

抗体已成为生物治疗的主要类别,但传统的筛选方法在确定候选先导抗体时面临着时间和资源方面的巨大挑战。将高通量测序与计算方法相结合,标志着抗体发现领域取得了关键性进展,拓展了抗体的探索空间。在这一背景下,体外展示文库中使用的单链可变片段(scFvs)的全长测序取得了重大突破。然而,很少有工具能解决注释成对的重链和轻链可变结构域(VH 和 VL)的任务,而这正是全 scFv 测序的主要优势。为了填补这一方法空白,我们推出了 Seq2scFv,这是一种新型开源工具包,专门用于分析长读数测序平台的体外展示文库。Seq2scFv 有助于识别和彻底鉴定 VH 和 VL 区域的 V(D)J 重组。除了提供带注释的 scFv、翻译序列和编号链外,Seq2scFv 还能进行连接子推断和特征描述、使用唯一标识符进行序列编码以及对各轮选择中的相同序列进行量化,从而简化富集鉴定。我们预计,Seq2scFv 工具在抗体发现管道中的应用将有效加快展示文库的全面表征,并有可能促进高亲和性候选抗体的鉴定。
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引用次数: 0
Correction. 更正。
IF 5.6 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-01-01 Epub Date: 2024-10-20 DOI: 10.1080/19420862.2024.2416272
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引用次数: 0
Targeted protein degradation through site-specific antibody conjugation with mannose 6-phosphate glycan. 通过特定位点抗体与 6-磷酸甘露糖共轭实现靶向蛋白质降解。
IF 5.6 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-01-01 Epub Date: 2024-10-21 DOI: 10.1080/19420862.2024.2415333
Kaori Mukai, Robert Cost, Xin Sheen Zhang, Emily Condiff, Joanne Cotton, Xiaohua Liu, Ekaterina Boudanova, Björn Niebel, Peter Piepenhagen, Xinming Cai, Anna Park, Qun Zhou

Recent developments in targeted protein degradation have provided great opportunities to eliminating extracellular protein targets using potential therapies with unique mechanisms of action and pharmacology. Among them, Lysosome-Targeting Chimeras (LYTACs) acting through mannose 6-phosphate receptor (M6PR) have been shown to facilitate degradation of several soluble and membrane-associated proteins in lysosomes with high efficiency. Herein we have developed a novel site-specific antibody conjugation approach to generate antibody mannose 6-phosphate (M6P) conjugates. The method uses a high affinity synthetic M6P glycan, bisM6P, that is coupled to an Fc-engineered antibody NNAS. This mutant without any effector function was generated by switching the native glycosylation site from position 297 to 298 converting non-sialylated structures to highly sialylated N-glycans. The sialic acid of the glycans attached to Asn298 in the engineered antibody was selectively conjugated to bisM6P without chemoenzymatic modification, which is often used for site-specific antibody conjugation through glycans. The conjugate is mainly homogeneous by analysis using mass spectrometry, typically with one or two glycans coupled. The M6P-conjugated antibody against a protein of interest (POI) efficiently internalized targeted soluble proteins, such as human tumor necrosis factor (TNF), in both cancer cell lines and human immune cells, through the endo-lysosomal pathway as demonstrated by confocal microscopy and flow cytometry. TNF in cell culture media was significantly depleted after the cells were incubated with the M6P-conjugated antibody. TNF internalization is mediated through M6PR, and it is correlated well with cell surface expression of cation-independent M6PR (CI-MPR) in immune cells. A significant amount of CI-MPR remains on the cell surface, while internalized TNF is degraded in lysosomes. Thus, the antibody-M6P conjugate is highly efficient in inducing internalization and subsequent lysosome-mediated protein degradation. Our platform provides a unique method for producing biologics-based degraders that may be used to treat diseases through event-driven pharmacology, thereby addressing unmet medical needs.

靶向蛋白质降解领域的最新进展为利用具有独特作用机制和药理学的潜在疗法消除细胞外蛋白质靶点提供了巨大的机会。其中,通过 6-磷酸甘露糖受体(M6PR)发挥作用的溶酶体靶向嵌合体(LYTACs)已被证明能在溶酶体中高效降解多种可溶性蛋白和膜相关蛋白。在此,我们开发了一种新颖的位点特异性抗体共轭方法来生成抗体甘露糖-6-磷酸(M6P)共轭物。该方法使用一种高亲和力的合成 M6P 聚糖(bisM6P)与 Fc 工程抗体 NNAS 相结合。这种没有任何效应功能的突变体是通过将原生糖基化位点从 297 位切换到 298 位,将非糖基化结构转化为高度糖基化的 N-聚糖而产生的。工程抗体中连接到 Asn298 的聚糖的硅烷基酸被选择性地与双 M6P 结合,而无需进行化学酶修饰,化学酶修饰通常用于通过聚糖进行位点特异性抗体结合。通过质谱分析,共轭物主要是均匀的,通常有一个或两个聚糖偶联。共聚焦显微镜和流式细胞术证明,M6P 连接的感兴趣蛋白(POI)抗体可通过内溶酶体途径,在癌细胞系和人类免疫细胞中有效内化目标可溶性蛋白,如人类肿瘤坏死因子(TNF)。细胞与 M6P 结合物抗体孵育后,细胞培养基中的 TNF 明显减少。TNF 的内化是通过 M6PR 介导的,它与免疫细胞中阳离子非依赖性 M6PR(CI-MPR)的细胞表面表达密切相关。大量的 CI-MPR 保留在细胞表面,而内化的 TNF 则在溶酶体中降解。因此,抗体-M6P 共轭物在诱导内化和随后溶酶体介导的蛋白质降解方面非常有效。我们的平台为生产基于生物制剂的降解剂提供了一种独特的方法,这种降解剂可通过事件驱动药理学来治疗疾病,从而满足尚未得到满足的医疗需求。
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引用次数: 0
Insights into the mechanisms of serplulimab: a distinctive anti-PD-1 monoclonal antibody, in combination with a TIGIT or LAG3 inhibitor in preclinical tumor immunotherapy studies. 在临床前肿瘤免疫疗法研究中与 TIGIT 或 LAG3 抑制剂联合使用 Serplulimab(一种独特的抗 PD-1 单克隆抗体)的机制透视。
IF 5.6 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-01-01 Epub Date: 2024-11-04 DOI: 10.1080/19420862.2024.2419838
Yizhou Zhang, Ruicheng Wei, Ge Song, Xinyi Yang, Mengli Zhang, Wei Liu, Aiying Xiong, Xuehan Zhang, Qianhao Li, Wan-Jen Yang, Chencheng Han, Rui Liu, Chen Hu, Qingyu Wang, Jun Zhu, Yongqiang Shan

With more than 20 anti-PD-1/PD-L1 antibodies currently marketed, anti-PD-1 therapy has become a cornerstone of tumor immunotherapy. These agents, however, exhibit notable disparities in their characteristics and clinical performance. For instance, in the field of small cell lung cancer (SCLC) where the majority of anti-PD-1 antibodies have yielded limited success, serplulimab produced impressive survival improvements and was approved for this indication by China's National Medical Products Administration. Serplulimab's marketing authorization application also received a positive opinion from the European Medicines Agency. Nevertheless, the molecular mechanism underpinning serplulimab's superiority over its competitors remains elusive. We characterized the differences between serplulimab with approved PD-1/PD-L1 inhibitors (pembrolizumab and nivolumab) in terms of their binding features and functions in vitro and anti-tumor activity in vivo. Cellular pathways underlying the efficacy of serplulimab were also investigated. In comparison to competitors, serplulimab robustly induces PD-1 receptor endocytosis while fostering weaker PD-1-CD28 cis interactions. This phenomenon could mitigate the dephosphorylation of CD28 by SHP2, thereby facilitating sustained and robust T cell activation. While serplulimab and pembrolizumab exhibited similar performance in vitro and in vivo studies, serplulimab consistently demonstrated superior tumor killing efficacy compared to pembrolizumab upon co-administration with anti-TIGIT or anti-LAG3 inhibitors. Mechanistically, the serplulimab combination effectively reduces tumor microenvironment Treg cell populations, augments effector and memory T cell populations, and more potently modulates genes associated with diverse facets of the immune system, surpassing the effects of the pembrolizumab combination. In summary, our data underscore serplulimab as a differentiated PD-1 monoclonal antibody with best-in-class therapeutic potential.

目前已有 20 多种抗 PD-1/PD-L1 抗体上市,抗 PD-1 疗法已成为肿瘤免疫疗法的基石。然而,这些药物在特性和临床表现上存在明显差异。例如,在小细胞肺癌(SCLC)领域,大多数抗 PD-1 抗体的疗效有限,而 Serplulimab 的生存期改善令人印象深刻,并被中国国家医药产品监督管理局批准用于该适应症。Serplulimab 的上市许可申请也得到了欧洲药品管理局的肯定。然而,Serplulimab优于其竞争对手的分子机制仍未确定。我们从体外结合特征和功能以及体内抗肿瘤活性的角度,描述了 serplulimab 与已批准的 PD-1/PD-L1 抑制剂(pembrolizumab 和 nivolumab)之间的差异。此外,还研究了serplulimab疗效的细胞通路。与竞争对手相比,serplulimab能强有力地诱导PD-1受体内吞,同时促进较弱的PD-1-CD28顺式相互作用。这种现象可减轻SHP2对CD28的去磷酸化作用,从而促进T细胞的持续和稳健活化。虽然 serplulimab 和 pembrolizumab 在体外和体内研究中表现出相似的性能,但在与抗 TIGIT 或抗 LAG3 抑制剂联合用药时,与 pembrolizumab 相比,serplulimab 始终表现出更高的肿瘤杀伤效力。从机理上讲,serplulimab 联合用药可有效减少肿瘤微环境 Treg 细胞群,增加效应和记忆 T 细胞群,并更有效地调节与免疫系统不同方面相关的基因,其效果超过了 pembrolizumab 联合用药。总之,我们的数据强调了 serplulimab 是一种差异化的 PD-1 单克隆抗体,具有同类最佳的治疗潜力。
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