排名前五的靶点	数量

HIV-1 nef(HIV-1 Nef蛋白)	9
AR-v7(雄激素受体剪接变异体7)	2
12/15-LOX x PEBP1	2
Kv1.1(电压门控性钾通道蛋白亚型Kv1.1)	1
XKR8(XK related 8)	1

关联

项与 University of Pittsburgh 相关的药物

Metformin Hydrochloride

盐酸二甲双胍

靶点

PRKAB1

作用机制

PRKAB1激活剂

在研机构

National Cancer Institute [+32]

原研机构

Bristol Myers Squibb Co.

在研适应症

糖尿病 [+50]

非在研适应症

腺泡细胞癌 [+72]

最高研发阶段批准上市

首次获批国家/地区

中国

首次获批日期1992-01-01

Curcumin

姜黄素

靶点

DNMT1 x MDM2 x Nrf2 x RBM3 x TGF-β x TLR4 x VEGF

作用机制

DNMT1抑制剂 [+6]

在研机构

The University of Texas MD Anderson Cancer Center [+42]

原研机构

The University of Texas MD Anderson Cancer Center

在研适应症

炎症 [+37]

非在研适应症

变异结肠腺窝病灶 [+7]

最高研发阶段批准上市

首次获批国家/地区-

首次获批日期-

Fluorouracil

氟尿嘧啶

靶点

TYMS

作用机制

TYMS抑制剂

在研机构

NRG Oncology [+28]

原研机构

Spectrum Pharmaceuticals, Inc.

在研适应症

食管癌 [+99]

非在研适应症

胆道腺癌 [+113]

最高研发阶段批准上市

首次获批国家/地区

美国

首次获批日期1962-04-25

2,425

项与 University of Pittsburgh 相关的临床试验

NCT06956352

/ Not yet recruitingN/AIIT

Impact of Collaborative Care for Pregnant Women With Opioid Use Disorder in Low-Resource Obstetric Settings

The investigators seek to adapt a collaborative care model (CCM) for community-based, low-resource obstetric settings and to test the effects of this adapted CCM on health outcomes among Pregnant, postpartum, and parenting person (PPPP) with Opioid use disorder (OUD) and their families. To achieve this goal, investigators will conduct a nonrandomized, Type 1 hybrid implementation-effectiveness study across 3 community-based, low-resource obstetric sites in Northwest PA, a region with rates of maternal opioid-related diagnoses 4 times higher than national averages.

开始日期2026-08-01

申办/合作机构

University of Pittsburgh

[+2]

NCT05091593

/ WithdrawnN/AIIT

A Hybrid Type I Randomized Effectiveness-Implementation Trial of Remote Treatment of Depression in Rural Community Cancer Centers

In an effort to reduce rural-urban disparities and improve the quality of cancer care for these patients, the objectives of this study will be to: (1) adapt the intervention to maximize effectiveness for rural, low-income patients, (2) test the effectiveness of the adapted intervention, and (3) prepare for implementation of the intervention in rural, low-income communities.

开始日期2026-06-01

申办/合作机构

University of Pittsburgh

[+1]

NCT05612399

/ Not yet recruitingN/AIIT

Precision Perioperative Methadone Use in Adult Cardiac Surgical Patients to Reduce Opioid Use Adverse Effects While Improving Analgesia and Outcomes

The proposed research is an important extension of an ongoing perioperative personalized analgesia and intravenous opioid pharmacogenetic research. This research focuses on two of the most commonly used oral opioid analgesics, oxycodone, and methadone in elderly adults undergoing cardiac surgery.

开始日期2026-04-01

申办/合作机构

University of Pittsburgh

100 项与 University of Pittsburgh 相关的临床结果

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0 项与 University of Pittsburgh 相关的专利（医药）

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87,281

项与 University of Pittsburgh 相关的文献（医药）

2025-12-31·Emerging Microbes & Infections

Eurasian 1C swine influenza A virus exhibits high pandemic risk traits

Article

作者: Drapeau, Elizabeth M. ; Rockey, Nicole C. ; Le Sage, Valerie ; Doyle, Joshua D. ; Arruda, Bailey ; Barbeau, Dominique J. ; Shephard, Meredith ; Lakdawala, Seema S. ; Souza, Carine K. ; Hensley, Scott E. ; Paulson, James C. ; Vincent Baker, Amy L. ; Wang, Shengyang ; Xu, Lingqing ; Anderson, Tavis K. ; McElroy, Anita K. ; Zanella, Giovana C.

ABSTRACTRecent surveillance has identified an expansion of swine H1 1C influenza viruses in Eurasian swine. Since 2010, at least 21 spillover events of 1C virus into humans have been detected and three of these occurred from July to December of 2023. Pandemic risk assessment of H1 1C influenza virus revealed that individuals born after 1950 had limited cross-reactive antibodies, confirming that they are antigenically novel viruses. The 1C virus exhibited phenotypic signatures similar to the 2009 pandemic H1N1 virus, including human receptor preference, productive replication in human airway cells, and robust environmental stability. Efficient inter- and intraspecies airborne transmission using the swine and ferret models was observed, including efficient airborne transmission to ferrets with pre-existing human seasonal H1N1 immunity. Together our data suggest H1 1C influenza virus poses a relatively high pandemic risk.

2025-12-31·OncoImmunology

Assessment of adenosinergic activity of small extracellular vesicles in plasma of cancer patients and healthy donors

Article

作者: Menchikova, Elizabeth V. ; Jackson, Edwin K. ; Whiteside, Theresa L. ; Najjar, Yana ; Hong, Chang Sook

The adenosinergic pathway converting endogenous ATP to adenosine (ADO) is a major immunosuppressive pathway in cancer. Emerging data indicate that plasma small extracellular vesicles (sEV) express CD39 and CD73 and produce ADO. Using a noninvasive, highly sensitive newly developed assay, metabolism of N⁶-etheno-labeled eATP, eADP or eAMP by ecto-nucleotidases on the external surface of sEV was measured using high pressure liquid chromatography with fluorescence detection. Ecto-nucleotidase activity in sEV isolated from plasma of randomly selected cancer patients and healthy donors (HDs) was compared. Relative to sEV of HDs, sEV from the plasma of melanoma patients metabolized eATP to eADP and eAMP to eADO with significantly greater efficiency. Activities of both CD39 and CD73 were elevated, as determined by the use of pharmacologic inhibitors selective for these enzymes. In contrast, metabolic activity of CD39 and CD73 on sEV isolated from plasma of patients with head and neck cancer was comparable to that of HDs, suggesting that the activity of ecto-nucleotidases on sEV may differ depending on the cancer type or cancer stage. The N⁶-etheno-purine assay measuring contributions of ecto-nucleotidases residing on the surface of sEV to the extracellular ATP to ADO pathway can discriminate cancer patients from HDs, differentiate among different cancer types, and potentially identify patients most likely to benefit from anti-adenosinergic therapy designed to inhibit the adenosine-mediated immune suppression.

2025-12-31·HYPERTENSION IN PREGNANCY

Identifying the timing and type of inflammatory markers for potential prediction of preeclampsia in women with obesity

Article

作者: Helsabeck, Nathan P ; Conley, Yvette P ; Roberts, James M ; Jancsura, McKenzie K ; Anderson, Cindy M ; Hubel, Carl A

BACKGROUND:

Preeclampsia is a leading contributor to maternal and infant mortality, and early risk identification is a high priority. Inflammatory markers have shown potential as biomarkers for preeclampsia prediction, though optimal timing and marker selection remain unclear.

METHODS:

We measured 20 inflammatory markers using the Luminex platform across all three trimesters in 37 participants who developed preeclampsia and 74 normotensive controls, matched for pre-pregnancy body mass index (>25), smoking status, and race. We examined individual markers by trimester, changes in marker levels between trimesters, and ratios of pro- to anti-inflammatory markers, adjusting analyses for maternal age, gestational age, and fetal sex.

RESULTS:

First-trimester levels of proinflammatory cytokines (GM-CSF, IFN-α, IFN-γ, IL-1α, IL-1β, IL-8, IL-12p70, IL-17a, TNF-α) and anti-inflammatory cytokines (IL-4, IL-10, and IL-13) were strongly associated with preeclampsia (standardized odds ratios > 2). First-trimester pro-anti-inflammatory ratios (e.g. TNF-α:IL-10 and IFN-γ:IL-10) also correlated with preeclampsia. Changes in inflammatory markers across trimesters and interactions with fetal sex were not significant.

CONCLUSION:

Our results suggest that the first trimester inflammatory markers and ratios may offer utility for preeclampsia prediction. Future research should explore these associations in diverse populations and validate their clinical utility. Early risk identification can inform interventions to prevent preeclampsia and improve perinatal outcomes.

767

项与 University of Pittsburgh 相关的新闻（医药）

2025-07-06

·ioncology

乳腺癌对德曲妥珠单抗耐药怎么办

点击蓝字，关注我们近年来，抗体缀合药物德曲妥珠单抗已经成为治疗HER2表达乳腺癌的大杀器，不论HER2高表达、低表达还是超低表达。不过，仍有大约25%至50%的患者对此药完全无效或者继发耐药。2025年6月27日，英国《自然》旗下《自然癌症》在线发表美国梅奥（妙佑）医学中心、匹兹堡大学、NSABP基金会、哈佛大学医学院达纳法伯癌症研究所、康奈尔大学、佛罗里达大学、中国清华大学、芬兰赫尔辛基大学的研究报告，发现这些对德曲妥珠单抗耐药的HER2阳性乳腺癌能够表达比普通HER2短一截的p95HER2引起免疫逃逸，从而促进肿瘤生长并产生德曲妥珠单抗耐药，问世十多年来命运坎坷的奈拉替尼对此有效。这源于p95HER2具有促进乳腺癌细胞表达程序性死亡配体PD-L1让人体免疫细胞进入自杀程序并分泌白细胞介素IL-6等免疫抑制介质的独特能力。对于临床前模型，这可削弱德曲妥珠单抗的疗效，因为其完全疗效依赖于对细胞死亡的免疫原反应。重要的是，该研究发现奈拉替尼能够有效引导蛋白酶体降解p95HER2，从而减轻其免疫抑制作用。该研究对此概念进行验证，表明奈拉替尼±p95HER2下游介质靶向药物可以恢复人体抗肿瘤免疫力和德曲妥珠单抗的疗效。因此，该研究结果表明，p95HER2能够引起HER2阳性乳腺癌的免疫抑制程序和耐药机制，奈拉替尼可以靶向p95HER2，对于改善抗体缀合药物或者肿瘤免疫治疗药物的疗效具有潜在价值。Nat Cancer. 2025 Jun 27. IF: 28.5p95HER2, a truncated form of the HER2 oncoprotein, drives an immunosuppressive program in HER2(+) breast cancer that limits trastuzumab deruxtecan efficacy.Hu D, Lyu X, Li Z, Ekambaram P, Dongre A, Freeman T, Joy M, Atkinson JM, Brown DD, Cai Z, Carleton NM, Crentsil HE, Little J 4th, Kemp F, Klei LR, Beecher M, Sperinde J, Huang W, Joensuu H, Srinivasan A, Pogue-Geile KL, Wang Y, Feng H, Eli LD, Lalani AS, Zou J, Tseng GC, Bruno TC, Lee AV, Oesterreich S, Wolmark N, Allegra CJ, Jacobs SA, McAllister-Lucas LM, Lucas PC.Mayo Clinic, Rochester, MN, USA; University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; UPMC Hillman Cancer Center, Pittsburgh, PA, USA; BlueSphere Bio, Pittsburgh, PA, USA; NSABP Foundation, Inc., Pittsburgh, PA, USA; University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA; School of Medicine, Tsinghua University, Beijing, China; Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Cornell University, Ithaca, NY, USA; Monogram Biosciences, Laboratory Corporation of America Holdings, South San Francisco, CA, USA; Puma Biotechnology, Los Angeles, CA, USA; University of Florida Health, Gainesville, FL, USA; Comprehensive Cancer Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.Resistance to human epidermal growth factor receptor 2 (HER2)-targeted therapies and immuno-oncology agents poses a major challenge in treating HER2-positive breast cancer. Here we demonstrate that p95HER2, a truncated form of HER2, drives immune evasion in HER2-positive female breast cancer, enhancing tumor growth and conferring therapy resistance. This stems from the unique ability of p95HER2 to promote cancer cell-intrinsic programmed death ligand 1 expression and secretion of immunosuppressive mediators including interleukin 6. In preclinical models, this impairs the efficacy of trastuzumab deruxtecan, a HER2-directed antibody-drug conjugate (ADC) that relies on immunogenic responses to cell death for full efficacy. Importantly, we find that neratinib potently directs proteasomal degradation of p95HER2, relieving its immunosuppressive effects, and provide proof of concept that neratinib and/or agents targeting p95HER2 downstream mediators can restore antitumor immunity and trastuzumab deruxtecan efficacy. This study reveals a p95HER2-specific therapy resistance mechanism in HER2-positive female breast cancer and highlights the potential value of targeting p95HER2 to improve outcomes with ADCs or immuno-oncology agents.PMID: 40579589DOI: 10.1038/s43018-025-00969-4（来源：SIBCS）声明凡署名原创的文章版权属《肿瘤瞭望》所有，欢迎分享、转载。本文仅供医疗卫生专业人士了解最新医药资讯参考使用，不代表本平台观点。该等信息不能以任何方式取代专业的医疗指导，也不应被视为诊疗建议，如果该信息被用于资讯以外的目的，本站及作者不承担相关责任。

免疫疗法临床研究

2025-07-04

·DrugAI

Adv. Sci. | AntiBMPNN：用于精准抗体工程的结构引导图神经网络

DRUGAI本文介绍一篇来自深圳理工大学的冯志炜教授和薛颖教授、浙江大学侯廷军教授、浙江工业大学陈艳教授及匹兹堡大学的李威教授联合发表的研究。该研究提出了 AntiBMPNN，一种基于结构引导的图神经网络方法，能够在抗体工程中进行精确的序列设计并提升结合亲和力。AntiBMPNN 基于细化后的 message-passing neural network（MPNN）架构，结合抗体专属的三维结构数据，并使用频率驱动的打分函数与 AlphaFold 3 相协作，实现序列设计与结构恢复。通过该方法，模型在 perplexity 指标上达到了约 1.5，序列恢复率超过 80%，显著优于 ProteinMPNN方法。此外，研究还提出了一种频率基础的排序函数，用于评估候选序列的结构保真度、位置稳定性及生化特性，并通过 AlphaFold 3 验证结构重建品质。这种创新设置使得 AntiBMPNN 在单点突变设计中实验验证成功率高达 75%。在具体任务中，AntiBMPNN 相较于 AbMPNN、AntiFold 和 ProteinMPNN 在 CDR1–3 区域的设计表现优异，表明 AntiBMPNN 设计的序列性能显著超过原始序列和现有方法，突出了其在治疗性抗体设计中的实用潜力。研究背景在现代医学领域，抗体已成为至关重要的治疗工具，在癌症、自身免疫疾病和传染病等广泛疾病领域表现出显著疗效。传统抗体序列设计主要依赖实验方法，过程繁琐且耗时费力。近年来，计算抗体设计方法成为优化抗体功能与特异性的有效途径。该方法主要聚焦于对抗体结构中的关键氨基酸进行定向改造，而非进行大规模的序列改变。一种常见策略是在现有抗体结构中引入特定氨基酸，以此增强抗体与抗原的亲和力及选择性。另一种策略则是通过探索不同互补决定区（CDR）环的构象与序列，提升抗体识别抗原的能力。此外，以Rosetta为代表的序列设计算法，能够预测抗体与抗原之间的结构及能量相互作用，进而优化关键氨基酸，显著提高抗体与靶标表位的结合能力。随着深度学习技术的蓬勃发展，ProteinMPNN等新型工具在蛋白质结构预测和优化领域取得重大突破。然而，ProteinMPNN在抗体超变区序列预测的准确率仅约为40%，这表明抗体设计领域仍面临诸多挑战。为克服这些难题，专门针对抗体结构的AbMPNN模型通过精细优化的训练，在超变区序列恢复率和结构聚类方面表现突出。AntiFold工具则利用反向折叠方法和抗原信息，大幅提升了抗体序列恢复与亲和力预测的准确性。尽管如此，这些方法目前缺乏充分的实验验证。而IgDesign作为首个经实验验证的抗体逆向折叠模型，成功设计了针对多个治疗靶点的抗体序列，并通过实验验证表现优于传统方法。然而，其代码未公开，这在一定程度上限制了更广泛的评估。最新提出的RFantibody流水线整合了多个先进工具，实现了抗体的从头设计，然而，设计过程的复杂性以及高昂的验证成本，仍是亟待解决的突出问题。方法概述本研究提出了名为AntiBMPNN的深度学习框架，专门用于优化抗体序列设计。它通过利用特制的抗体3D数据集、经过精细调整的消息传递神经网络（MPNN）、基于频率的评分函数以及AlphaFold 3，从而实现了高精度的抗体序列设计（图1）。与ProteinMPNN相比，AntiBMPNN表现出显著优势，体现为更低的困惑度（1.5）和更高的序列恢复率（≥80%）。实验结果显示，AntiBMPNN在单点抗体设计中成功率高达75%。在大多数情形下，AntiBMPNN的表现优于现有方法，包括AbMPNN、AntiFold以及ProteinMPNN，在优化互补决定区（CDRs）的CDR1、CDR2和CDR3序列时均表现出更好的结合亲和力。在NanoJ3体系中，AntiBMPNN对CDR1区域进行优化后，获得的EC50为9.2 nM，明显优于ProteinMPNN的135.2 nM和AntiFold的59.3 nM，与AbMPNN（EC50为6.6 nM）表现相当。在D6抗体的CDR2区域，AntiBMPNN取得了0.3 nM的EC50，表现明显优于AbMPNN（2.3 nM）、AntiFold（0.7 nM）和ProteinMPNN（0.7 nM）。对于J3的CDR3区域，AntiBMPNN实现了1.7 nM的EC50值，明显优于AbMPNN（51.2 nM）、AntiFold和ProteinMPNN（后两者均未检测到明显的结合能力）。以上结果充分展现了AntiBMPNN在设计高亲和力抗体序列上的突出能力，表明该方法在抗体序列优化中具有重要的实用价值。结果与讨论图1. AntiBMPNN算法框架和性能表现。AntiBMPNN的训练性能在6578 个抗体结构的训练数据上比较不同骨架噪声水平时，AntiBMPNN 在无噪声（0 级）条件下取得最高准确率和最低困惑度。当噪声进一步增大到 0.4-1 时，模型准确率持续下降，显示出对数据噪声的敏感性，强调了预处理和质量控制对抗体结构预测的重要性。在另一项包含 120 个 3D 结构（H+L 链、H 链、L 链）的综合测试中，AntiBMPNN 的中位序列恢复率分别为 88.09%、81.31% 和 94.16%，显著优于 ProteinMPNN（分别为 55.32%、50.84%、54.79%）。此外，AntiBMPNN 的序列恢复率与残基埋藏度呈正相关：深埋核心可达 93%-97%，表面区域为 85%-91%。针对六条 CDR 环（CDRH1、CDRH2、CDRH3、CDRL1、CDRL2、CDRL3）的比较显示，AntiBMPNN 在 CDRH1、CDRH3、CDRL1 和 CDRL2 四条环上取得最高恢复率（0.7358、0.5800、0.8129、0.8259）；AntiFold 则在 CDRH2 和 CDRL3 略占优势。总体来看，所有模型在轻链环上的恢复率普遍高于重链环，而 CDRH3 仍是最具挑战的区域（最高仅 0.4314），反映了其序列设计的复杂性。参数对AntiBMPNN性能的影响在对训练噪声水平与采样温度的影响进行评估时，作者发现 AntiBMPNN 与 ProteinMPNN 呈现相似的趋势：随着噪声或温度升高，两者的序列恢复率均持续下降。AntiBMPNN 在三种测试集上的最低平均恢复率约为 60%，而 ProteinMPNN 仅约 30%，说明高噪声或高温度会削弱模型准确复现序列的能力，但也可能有利于生成更多样的新序列。图 2 则展示了测试序列与训练序列相似性对恢复率的影响。在 40 条 H 链和 40 条 L 链晶体/冷冻电镜结构上，作者计算了序列相似度并用线性回归绘制趋势线，得出较高的皮尔逊相关系数：H 链约 0.80、L 链约 0.65。结果表明，相似度越高，序列恢复越好，说明 AntiBMPNN 对已见过的序列片段表现更可靠，对全新或高度变异序列的泛化能力则相对受限。进一步实验表明，将骨架噪声或采样温度中的任一参数固定在 0.5（中等且稳定）并调节另一参数，可显著提升 H 链与 L 链的恢复表现。这表明适度而稳定的噪声或温度（≈0.5）有助于优化 AntiBMPNN 的序列恢复率。值得注意的是，虽然 L 链整体恢复率高于 H 链，H 链的恢复率与序列相似度的相关性更强，暗示两类链在相似度对恢复效果的敏感度上存在差异。图2. 序列相似性对 AntiBMPNN 和 ProteinMPNN 序列恢复的影响。基于频率的评分函数和 AlphaFold 3 用于序列选择AntiBMPNN 在不固定或固定指定残基的情况下批量生成序列，但因相同序列恢复率下仍会出现大量重复序列且评分差异大，用户难以挑选。为此，作者设计了基于出现频次的评分函数（流程见图3a）：先按全长序列聚类，再用各序列在全集中的出现次数排序。以抗体 huJ3 为例，AntiBMPNN 仅在 CDR3 的六个位点（K97、I101、Y103、N104、S105、N106）进行设计，生成 32768 条序列，最终归为 147 个簇。出现频次最高的序列 “ARSKSTYLSRDSSGYDY”（位点 94-110）出现 6495 次，与原序列相比在 I101、Y103、N104、N106 四处发生替换，整体序列恢复率为 0.67。频次统计与各突变位点的化学性质分布（图 3b,c）直观展示了模型的偏好，便于筛选候选序列。随后作者用 AlphaFold 3 进一步评估高排名序列的结构可靠性与抗原结合潜力：先在单体模式下为每条抗体序列生成 5 个模型，取最高 pLDDT 分值的模型代表其自我折叠可能性；再与相应抗原（如 gp120）联合建模生成 5 个复合物模型，取 ranking_score 最高者代表其结合构象（图3d）。每种建模方法 pLDDT 或 ranking_score 最优的 1–2 条序列被选入后续实验验证。图3. AntiBMPNN和AlphaFold3中的评分函数的集成,对每个设计序列的候选进行排序使用 AntiBMPNN 进行单点序列设计并进行实验验证作者将人源化的骆驼纳米抗体 huJ3为例，其中 CDR3（位点94-110）的 “ARSKSTYISYNSNGYDY” 片段尤为关键；既往研究已指出其中 “STY” 三肽（位点 98–100）对配体结合极为敏感。为开展序列设计，作者首先以 PDB 7ri1 中的 J3 结构为模板，构建了 huJ3 及其与抗原 gp120 的复合物三维模型。随后聚焦 “SYNSN”（位点 102–106）进行单点突变设计并实验验证。AntiBMPNN 预测的最高频替换为 S102S（保持不变，99.0%）、Y103R（90.2%）、N104S（99.7%）、S105P（98.4%）和 N106S（>99.9%）；同时也探索了 S102N、N104A、N104M 与 Y103H 等低频变体。八个单点设计中有六个保持了与父本 huJ3 相当的亲和力（EC50=2.3-6.7 nM），包括 S105P、N106S、N104A、N104M、S102N、N104S；而 Y103H 使亲和力降低约 13 倍，Y103R 则几乎失去结合能力。这些计算与实验结果进一步验证了 AntiBMPNN 的可靠性，并为将其扩展至更广泛的抗体 CDR 设计提供了依据。使用 AntiBMPNN 进行 huJ3 CDR1 全长序列设计及实验验证研究者在骨架噪声 BN = 0.5、温度 T = 0.1 的条件下，针对 huJ3 抗体的 CDR1 区（26-33 位，基序 “GSIFNQYA”）进行全长序列设计。结果显示 26、27、29、32、33 位点（G、S、F、Y、A）高度保守，即使将 BN 提高到 0.7 仍保持不变，而 28、30、31 位（I、N、Q）则呈现较大可变性。基于评分函数和 AlphaFold 3，筛选出五条候选序列 1-V1 至 1-V5 进行实验验证。序列比对显示这些变体在 CDR1 的若干残基与对照（nanoJ3、huJ3）不同；ELISA 结果表明，1-V1 至 1-V4 的 EC50 介于 9.2-99.6 nM，1-V5 则未检测到结合活性。结构分析指出，Q31 常被小体积的甘氨酸取代导致接触不足，而 1-V1 通过 I28R 补偿，R28 与 D30 与 gp120 表面形成关键相互作用，因此亲和力最好（EC50 ≈ 9.2 nM）。相较之下，CDR1 对抗原结合的重要性通常低于 CDR3；下一步作者将利用 AntiBMPNN 方法设计 huJ3 的 CDR3 并进行实验验证。图4. AntiBMPNN设计的huJ3 CDR1的实验验证结果。使用 AntiBMPNN 进行 huJ3 CDR3（残基 94 至 105）序列设计并进行实验验证研究团队继续对 huJ3 抗体的 CDR3 区域进行定向设计，靶向 94-105 位残基（完整 CDR3 序列为 “ARSKSTYISYNSNGYDY”，94-110 位）。鉴于原始研究表明 “STY” 保守基序中的 T98R 与 Y99G 单点突变会完全失去结合活性，本次设计固定了 98-100 位的 “STY” 以保持功能。采用与 CDR1 相同的建模体系（huJ3-gp120 复合物，BN = 0.5，T = 0.1），结果发现 R95、K97、S102、N104、S105、N106 等位点可被多种氨基酸替换。依据评分函数与 AlphaFold 3，筛选出 11 条高分序列进行实验验证。实验显示，重设计获得的 3-V1 至 3-V9 的 EC50 值跨度大（1.7-418.9 nM）。其中 3-V1 的 EC50 为 1.7 nM，优于母本 huJ3（2.9 nM），其 H97、N102、S106 三个新引入残基与 gp120 形成关键相互作用。3-V3 的 H97、N102、S104 设计亦带来 6.6 nM 的 EC50，略低于 huJ3。相反，3-V10 与 3-V11 由于在关键位点（如 R95K、T99I、Y100R）做出不当改动，完全失去结合活性。整体结果进一步验证了 AntiBMPNN 在 CDR3 精准重设计中的有效性与挑战并存的特征。图5. AntiBMPNN 设计的 huJ3 CDR3 变体的实验验证结果.使用 AntiBMPNN 进行抗 CD16A VH 抗体 (D6) 的 CDR2 序列设计及实验验证为评估 AntiBMPNN 的稳健性和实用性，研究者将其用于靶向 CD16A 的单域抗体 D6（VH）的 CDR2 设计。首先构建了 D6 的 3D 结构，在 BN = 0.5、T = 0.1 条件下，针对 CDR2 基序 “SIYYSGSTN”（50-58 位）进行定向突变。结果显示 50、51、53、54、56 位残基较易被替换，而 52、55、57、58 位相对保守。考虑到 D6 原有的 R66L 变异不影响亲和力，设计时保留并与 CDR2 方案合并。依评分函数选出 2-V1 至 2-V4 四个候选体实验验证：序列比对显示关键差异；ELISA 结果与对照 D6 比较后，结构对接指出 Y53 对结合至关重要，其酚羟基与抗原表面高度互补，突变（2-V1、2-V4）显著降低亲和力；S50 则耐受性较高，适度延伸侧链可提高（2-V2）或不损伤（2-V3）亲和力。各变体 EC50 值如图 6d 所示，整体印证了 AntiBMPNN 在 CDR2 精准优化中的效能与位点敏感性。图6. AntiBMPNN 设计的 D6 CDR2 变体的实验验证结果。AntiBMPNN与现有基于实验数据的抗体序列设计方法的比较分析为了评估不同生成模型的性能，本研究首先以AntiBMPNN、ProteinMPNN和AbMPNN三种模型对CDR3区（97至106位氨基酸残基）进行了重新设计，保持关键“STY”序列不变。这些模型产生了含2至5个突变的变体，但所有设计序列均未保持可测量的结合活性，这强调了维持关键功能残基和严格控制突变范围的重要性。作者进一步对AntiBMPNN与AbMPNN、AntiFold和ProteinMPNN等方法进行了全面对比。针对huJ3体系，优化CDR1区的关键残基28、30、31位，AntiBMPNN设计的“RDG”序列取得了出色的结合亲和力（EC50为9.2 nm），优于其他模型。相较之下，AbMPNN设计的两个序列分别为非结合的“GSS”和较优的“PSK”（EC50为6.6 nm）；AntiFold最佳序列“TDN”的EC50为59.3 nm；ProteinMPNN设计的序列则表现更差（EC50分别为135.2 nm和无结合活性）。因此，AntiBMPNN在CDR1区优化中的表现显著优于其他模型。在D6抗体中，针对CDR2区的50和66位残基进行优化，AntiBMPNN设计的最佳序列“NR”达到了极低的EC50（0.3 nm），远优于其他模型。AbMPNN的“LG”序列无法在大肠杆菌中表达，“TG”序列EC50为2.3 nm；AntiFold最佳序列“SR”的EC50为0.7 nm，而ProteinMPNN表现欠佳（EC50超过1000 nm）。AntiBMPNN展现了在CDR2区优化上的高精准性和稳定优势。此外，huJ3的CDR3区优化（残基97、102、106位）中，AntiBMPNN设计的“HNS”序列实现了1.7 nm的优秀EC50，显著超过其他方法。AbMPNN设计的“GYG”和“SSS”序列效果较差（无结合和EC50为51.2 nm），AntiFold和ProteinMPNN也未取得有效结合。最后，本研究使用AlphaFold 3为所有设计序列及其抗原复合物生成了“ranking_score”，但发现这些结构可信度评分与实验测得的结合活性并不总是相关。例如，在huJ3再设计中，结构评分几乎相同的两个序列，其EC50值却差异超过一个数量级（6.6 nm和135.2 nm）。此外，D6抗体由于缺乏实验解析结构，导致AlphaFold 3的预测可信度较低。这表明仅依靠结构评分预测功能结果存在局限，需结合其他指标或实验验证。总结作者介绍了 AntiBMPNN，一种结构驱动的图神经网络框架，用于精准抗体设计与工程。该模型在特定的三维抗体结构数据集上进行微调，展示出卓越的序列恢复能力，并在多项基准测试中显著优于已有方法。作者进一步将其应用于人源化纳米抗体（如 huJ3）和其他抗体 CDR 区域的设计，为实验验证筛选出高亲和力候选序列，证明了模型的实用价值。此外，通过结合 AlphaFold 3 对候选序列进行结构与配体结合模拟，作者还提出了高效的筛选策略，为后续实验研究提供强有力的支持。总体而言，本研究构建了一个基于结构信息的深度学习平台，为抗体工程提供了精准设计的新路径。参考资料Ze-Yu Sun, Jiayi Yuan, Divya Jaiswal, Jingxuan Ge, Tianjian Liang, Jiahui Wei, Jinghong Cao, Yulong Li, Xiaojie Chu, Yan Chen*, Ying Xue*, Wei Li*, Tingjun Hou*, Zhiwei Feng*. AntiBMPNN: Structure-Guided Graph Neural Networks for Precision Antibody Engineering. Advanced Science, Published online June 27, 2025. doi:10.1002/advs.202504278

2025-06-26

·GlobeNewswire-Health Care

Coeptis (COEP) Announces Filing of Registration Statement on Form S-4 with SEC in Connection with Proposed Transaction with Z Squared

WEXFORD, Pa., June 26, 2025 (GLOBE NEWSWIRE) -- Coeptis Therapeutics Holdings, Inc. (Nasdaq: COEP) (“Coeptis” or the “Company”), a next-gen technology and biopharmaceutical company, is pleased to announce the filing of a registration statement on Form S-4 with the Securities and Exchange Commission ("SEC") related to the Company's previously announced and proposed definitive merger agreement (the "Merger") with Z Squared Inc. (“Z Squared”). The Form S-4 includes a preliminary proxy statement/prospectus regarding the proposed transaction. The registration statement has not yet become effective, and the information contained therein is subject to change. About Coeptis Therapeutics Holdings COEPTIS, Inc., together with its subsidiaries Coeptis Pharmaceuticals, Inc., GEAR Therapeutics, Inc., SNAP Biosciences, Inc., and Coeptis Technologies (collectively "Coeptis"), is a biopharmaceutical and technology company. The biopharmaceutical divisions focus on developing innovative cell therapy platforms for cancer, autoimmune, and infectious diseases. Coeptis aims to advance treatment paradigms and improve patient outcomes through its cutting-edge research and development efforts. The Company's therapeutic portfolio is underscored by assets licensed from Deverra Therapeutics, which include an allogeneic cellular immunotherapy platform and DVX201, a clinical-stage, unmodified natural killer cell therapy technology. COEPTIS is also developing a universal, multi-antigen CAR technology licensed from the University of Pittsburgh (SNAP-CAR), alongside GEAR cell therapy and companion diagnostic platforms in collaboration with VyGen-Bio and distinguished medical researchers at the Karolinska Institute. Building on its core competencies, COEPTIS has recently established a Technology Division, which focuses on enhancing operational capabilities through advanced technologies. This division features AI-powered marketing software and robotic process automation tools acquired from NexGenAI Solutions Group, designed to optimize business processes and improve overall efficiency. Headquartered in Wexford, PA, COEPTIS is dedicated to advancing its mission within the regulatory framework set forth by the FDA, ensuring that all activities align with the highest standards of compliance and patient care. For more information on COEPTIS, visit https://coeptistx.com. About Z Squared Z Squared Inc is an emerging leader in digital asset compute mining, focused on the generation of Dogecoin (DOGE), primarily, along with other digital assets such as Litecoin and other altcoins. Z Squared aims to unlock gainful investor mining exposure to DOGE, its $20B market cap, and the robust business of alt coin compute mining. Additional Information and Where to Find it This press release relates to a proposed merger transaction between Coeptis and Z Squared. This press release does not constitute an offer to sell or exchange, or the solicitation of an offer to buy or exchange, any securities, nor shall there be any sale of securities in any jurisdiction in which such offer, sale or exchange would be unlawful prior to registration or qualification under the securities laws of any such jurisdiction. In connection with the proposed transaction, Coeptis has filed relevant materials with the SEC including a registration statement on Form S-4, which includes a prospectus with respect to the combined company’s securities to be issued in connection with the proposed transaction and a proxy statement with respect to the stockholder meeting of Coeptis to vote on several proposals including the proposed transaction. Promptly after the registration statement is declared effective by the SEC, Coeptis will mail the definitive proxy statement/information statement/prospectus to each of its shareholders. Coeptis urges its investors, stockholders and other interested persons to read, when available, the preliminary proxy statement/information statement/prospectus as well as other documents filed with the SEC because these documents contain important information about Coeptis, Z Squared and the proposed transaction. The preliminary and definitive proxy statement/information statement/prospectus to be included in the registration statement, once available, can be obtained, without charge, at the SEC’s website (www.sec.gov). Participants in the Solicitation Coeptis, Z Squared and their respective directors, executive officers, other members of management and employees may be deemed participants in the solicitation of proxies from Coeptis’ and Z Squared’s stockholders with respect to the proposed business combination. Investors and securityholders may obtain more detailed information regarding the names and interests in the business combination of the directors and officers of each of Coeptis and Z Squared in such companies’ respective filings with the SEC, including the Form S-4. No Offer or Solicitation This press release shall not constitute a solicitation of a proxy, consent, or authorization with respect to any securities or in respect of the proposed business combination or spin out. This press release shall also not constitute an offer to sell or the solicitation of an offer to buy any securities, nor shall there be any sale of securities in any states or jurisdictions in which such offer, solicitation, or sale would be unlawful prior to registration or qualification under the securities laws of any such jurisdiction. No offering of securities shall be made except by means of a prospectus meeting the requirements of Section 10 of the Securities Act of 1933, as amended, or an exemption therefrom. Cautionary Note Regarding Forward-Looking Statements. This press release and statements of our management made in connection therewith contain "forward-looking statements" (as defined in Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended). Forward-looking statements include statements concerning our plans, objectives, goals, strategies, future events or performance, and underlying assumptions, and other statements that are other than statements of historical facts. When we use words such as "may," "will," "intend," "should," "believe," "expect," "anticipate," "project," "estimate" or similar expressions that do not relate solely to historical matters, we are making forward-looking statements. Forward-looking statements are not a guarantee of future performance and involve significant risks and uncertainties that may cause the actual results to differ materially and perhaps substantially from our expectations discussed in the forward-looking statements. These statements are subject to significant uncertainties and risks including, but not limited, to those risks contained in reports filed by Coeptis with the Securities and Exchange Commission (the "SEC"). For these reasons, among others, investors are cautioned not to place undue reliance upon any forward-looking statements in this press release. Additional factors are discussed in the Company's filings made or to be made with the SEC, which are available for review at www.sec.gov. We undertake no obligation to publicly revise these forward-looking statements to reflect events or circumstances that arise after the date hereof unless required by applicable laws, regulations, or rules. ContactsIR@coeptistx.com Source: Coeptis Therapeutics

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