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VICTORIA, British Columbia--( BUSINESS WIRE )-- ImmunoPrecise Antibodies Ltd. (the “Company” or “IPA”) (NASDAQ: IPA), ImmunoPrecise Antibodies Ltd. (the “Company” or “IPA”) (NASDAQ: IPA), an AI-driven biotherapeutic research and technology company, today proudly announces the clinical progress achieved with rabbit monoclonal antibodies designed and developed using IPA’s proprietary B Cell Select ® platform for the clinical-stage company, OncoResponse Inc. This achievement underscores IPA’s leadership as a Contract Research Organization creating high-quality therapeutic antibodies, while pioneering work in the field of rabbit monoclonal antibody development. These antibodies are rapidly gaining recognition as a unique tool in therapies due to their distinctive properties, advancing into clinical trials aimed at improving patient outcomes. OncoResponse’s Breakthrough in Cancer Treatment In a live presentation at the recent PEGS 2024 conference, OncoResponse shared exciting updates on two novel antibodies, OR502 and OR641, both of which were discovered and refined using IPA’s innovative B Cell Select ® platform: OR502, a novel, humanized anti-leukocyte immunoglobulin like receptor B2 (LILRB2) antibody, has successfully entered Phase I/II clinical trials, showing excellent safety profile, and is being evaluated for efficacy in treating advanced solid tumors. Preclinical models have demonstrated that OR502 is a best-in-class anti-LILRB2 antibody that reverses immunosuppression caused by myeloid cells in the TME. OR641, a novel, humanized dual antagonist antibody targeting both LILRB1 and LILRB2, has completed Cell Line Development and is undergoing IND-enabling studies. Preclinical models have demonstrated its superior ability to reverse immunosuppression caused by myeloid and lymphoid cells compared to other anti-LILRB1/2 antibodies. Driving Antibody Discovery and Design for Clinical Success IPA’s proprietary B Cell Select ® platform has been instrumental in the rapid design and discovery of antibodies that have advanced to clinical stages for numerous clients. By preserving the natural structure of antibodies, IPA’s technology supports optimal functioning of the therapies in a clinical setting. Through comprehensive testing and validation, the process ensures that these antibodies maintain their efficacy and reliability from the lab to the clinic. "At ImmunoPrecise Antibodies, our mission is not just to develop antibodies, but to redefine what’s possible in therapeutic interventions," said Dr. Jennifer Bath, President and CEO of IPA. "Our innovative platform, built on years of expertise, has consistently delivered antibodies with superior qualities, many of which are now advancing in clinical trials. This reflects our unwavering commitment to innovation and our strategic advantage in the market. We are proud to support our clients in bringing groundbreaking, life-changing treatments to patients around the world, reinforcing the long-term value of our technologies." Harnessing Rabbit B Cell Technology for Breakthrough Antibody Discovery The Rabbit B Cell platform, a rapidly advancing technology in therapeutic antibody development, played a pivotal role in the discovery process. This platform excels at generating high-affinity and highly specific rabbit monoclonal antibodies, a demand met with very limited providers in the market. IPA has successfully utilized their B Cell Select platform in over 200 antibody programs, achieving remarkable success against a variety of targets, including small molecules, peptides, and proteins. The distinctive properties of rabbit antibodies, combined with IPA’s expertise, have consistently led to the development of promising therapeutic candidates. Building on this success, IPA is now offering more complex therapeutic rabbit antibody campaigns as a partnering model, providing companies with greater flexibility in structuring their more complicated programs. Outlook The field of rabbit monoclonal antibody (mAb) therapeutics is advancing rapidly, driven by innovations in antibody engineering and humanization techniques. These advancements are making rabbit mAbs increasingly popular for human therapeutic use. The unique properties of rabbit antibodies, combined with IPA’s full-service technologies, such as in silico humanization, indicate a strong potential for more rabbit-derived mAbs to enter clinical trials and achieve approval in the coming years. The distinctive advantages of rabbit antibodies make them a promising foundation for future therapeutic development. As this technology progresses, IPA remains at the forefront, harnessing these innovations to bring new, effective treatments to the clinic, reinforcing our growing leadership in the industry. Dr. Kamal D. Puri, Chief Scientific Officer of OncoResponse, recognized IPA’s pivotal role in their success, praising the quality and reliability of IPA’s antibody discovery services. “We are thrilled to have worked with IPA to discover our lead therapeutic antibodies. The IPA team’s deep experience and know-how with a battery of customized, high-throughput discovery strategies has played a critical role in the successful discovery of our molecules with unsurpassed speed and efficiency,” said Kamal D. Puri, Chief Scientific Officer of OncoResponse. About OR502 LILRB2 is an immunoinhibitory receptor expressed on tumor-associated macrophages (TAMs) found in the tumor microenvironment (TME). TAMs inhibit the activity of checkpoint inhibitor (CPI) therapy and prevent T cells from killing tumors. Blocking the inhibitory activity of TAMs and promoting the activity of tumor-killing T cells reverses inhibition of CPI therapy, potentially leading to more and deeper responses to CPIs in patients. This is the mechanism of OR502, which modulates LILRB2 by blocking its engagement of HLA-G on tumor cells and prevents the suppression of the myeloid cells. Elevated expression of LILRB2 correlates with reduced patient survival in various tumor types. This humanized monoclonal antibody, OR502, targets LILRB2 and blocks the inhibitory activity of TAMs and promotes the activity of tumor-killing T cells, reversing inhibition of CPI therapy. About OncoResponse OncoResponse is a clinical-stage, immuno-oncology biotech company developing cancer immunotherapies using clues from the immune systems of Elite Cancer Responders. In a broad strategic alliance with MD Anderson Cancer Center, OncoResponse deploys a proprietary B-cell discovery platform to identify and develop novel antibodies targeting immune cells in the tumor microenvironment. The company’s lead clinical candidate, OR502 is a best-in-class anti-LILRB2 antibody that rescues innate and adaptive immune responses from LILRB2-mediated immune suppression and has entered clinical study in 2023. OR502 clinical studies are being conducted with support from the Cancer Prevention Research Institute of Texas (CPRIT) DP230076. Additional pipeline candidates that modulate suppressive macrophage activity are under development, including OR641, a unique dual anti-LILRB2/1 antagonist antibody that promotes a Th1-like immune response. For more information, please visit www.oncoresponse.com and follow us on LinkedIn and X. About ImmunoPrecise Antibodies Ltd. ImmunoPrecise Antibodies Ltd. is a biotechnology company that leverages multi-omics modeling and complex artificial intelligence through a series proprietary and patented technologies. The Company owns an integrated end-to-end suite of capabilities to support the development of therapeutic antibodies and are known for solving very complex industry challenges. IPA has several subsidiaries in North America and Europe including entities such as Talem Therapeutics LLC, BioStrand BV, ImmunoPrecise Antibodies (Canada) Ltd. and ImmunoPrecise Antibodies (Europe) B.V. (collectively, the “IPA Family”). Forward-Looking Statement This news release contains forward-looking statements within the meaning of applicable United States securities laws and Canadian securities laws. Forward-looking statements are often identified by the use of words such as “potential”, “plans”, “expects” or “does not expect”, “is expected”, “estimates”, “intends”, “anticipates” or “does not anticipate”, or “believes”, or variations of such words and phrases or state that certain actions, events or results “may”, “could”, “would”, “might” or “will” be taken, occur or be achieved. Forward-looking information contained in this news release includes, but is not limited to, statements relating to the expected outcome on the market, the life sciences, drug discovery and development, and clinical readiness or effectiveness of IPA-discovered therapeutics. In respect of the forward-looking information contained herein, IPA has provided such statements and information in reliance on certain assumptions that management believed to be reasonable at the time, those assumptions include: the continued successful of IPA’s technology in discovering and developing antibodies, timely regulatory approval and acceptance of therapies developed using the Company’s technologies, the potential for partnerships in antibody discovery and development; and the expectation that these technological advancements will drive increased revenue streams and sustained financial growth for the Company. Forward-looking statements involve known and unknown risks, uncertainties and other factors which may cause the actual results, performance or achievements stated herein to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements. Actual results could differ materially from those currently anticipated due to a number of factors and risks, as discussed in the Company’s Annual Report on Form 20-F for the year ended April 30, 2024 (which may be viewed on the Company’s SEDAR+ profile at www.sedarplus.ca and EDGAR profile at www.sec.gov/edgar ). Should one or more of these risks or uncertainties materialize, or should assumptions underlying the forward-looking statements prove incorrect, actual results, performance, or achievements may vary materially from those expressed or implied by the forward-looking statements contained in this news release. Accordingly, readers should not place undue reliance on forward-looking statements contained in this news release. The forward-looking statements contained in this news release are made as of the date of this release and, accordingly, are subject to change after such date. The Company does not assume any obligation to update or revise any forward-looking statements, whether written or oral, that may be made from time to time by us or on our behalf, except as required by applicable law.

*仅供医学专业人士阅读参考 提问：癌症和妊娠之间有什么关系？实话说，奇点糕的第一反应还是多年前在临床上，见到过的几例孕期确诊癌症的患者，但从癌症和免疫的角度去想，答案就完全不一样了：妊娠过程中存在母-胎免疫耐受，而癌细胞逃避免疫系统的追杀也是免疫耐受，近年来学界已经揭示了多个癌症与妊娠共享的免疫耐受机制和调控通路[1]，但还有不少机制藏在水下。 近日，密歇根大学邹伟平教授团队主导、耶鲁大学陈列平教授等研究者参与的一项最新研究成果登上了《细胞》，首次揭示免疫检查点分子B7-H4也参与了癌胚免疫耐受（Onco-fetal immune tolerance）：B7-H4的表达水平会受孕激素调控，并通过抑制CD8+T细胞激活和促耗竭帮助乳腺癌进展，研究还找到了调控上述进程的PR-P300-BRD4信号轴[2]。 论文核心机制总结 研究者们首先分析了14个不同肿瘤的单细胞RNA测序数据集，重点评估MHC分子、B7家族成员和肿瘤坏死因子（TNF）家族成员在癌细胞和滋养层细胞（胎盘主要成分）的表达特点，而B7-H4就是癌细胞表达水平最高、胎盘滋养层细胞表达水平第二高的基因，且乳腺癌、卵巢癌、子宫内膜癌等源自女性生殖器官的癌症中表达更是高得非常突出。 而对孕早期人体滋养层细胞转录组学的分析也显示，滋养层细胞会同时表达HLA-G和B7-H4，在小鼠胎盘中也是如此，且母体和胎儿起源的细胞和组织中均有B7-H4表达。结合B7-H4此前被推定的免疫抑制功能，研究者们初步猜测B7-H4是癌胚免疫耐受检查点，并通过小鼠实验来明确B7-H4的实际功能。 敲除雌性小鼠的B7-H4，并构建异基因交配模型后，研究者们观察到敲除B7-H4小鼠的胚胎吸收较未敲除小鼠更多，且胎盘及被吸收胚胎周围的蜕膜区域T细胞浸润显著增多，提示T细胞激活的标志物（如CD25/44/69）和多种趋化因子、细胞因子（如IFN-γ、TNF-α）水平也明显上升，说明B7-H4对异基因交配相关的免疫激活有调节作用。 进一步实验显示，CD8+T细胞对敲除B7-H4小鼠的胚胎吸收至关重要，而表达B7-H4的绒毛外滋养层细胞（EVTs）或是通过约束CD8+T细胞，使正常的母-胎免疫耐受能够存在，因此B7-H4起到了重要的保护作用，但放到癌症场景中情况就不同了。结合前面的实验，研究者们推测B7-H4在胎盘和癌症中的表达水平，可能受某种女性特有激素的调控。 B7-H4能调节母-胎免疫耐受 研究者们用三类不同的女性激素，即性激素（雌激素/孕激素）、妊娠相关激素（如绒毛膜促性腺激素/hCG）和月经周期相关激素（如卵泡刺激素/FSH）分别处理了乳腺癌细胞，发现仅有孕激素（孕酮）或孕酮受体激动剂处理可显著上调癌细胞的B7-H4表达，处理滋养层细胞和卵巢癌细胞的结果也是一样，但前列腺癌细胞或PD-L1表达就不会受孕酮影响。 而与此前小鼠交配模型中的现象一致，癌细胞的B7-H4表达被孕酮上调后，B7-H4就会抑制CD8+T细胞的抗肿瘤功能，加速乳腺癌在小鼠身上的进展，这种效应同时体现在两个方面，一方面是CD8+T细胞的增殖能力、细胞毒性功能都明显减弱，另一方面则是耗竭CD8+T细胞的占比明显上升。下一个问题就呼之欲出了：孕酮是怎么调控B7-H4表达的呢？ 孕酮上调B7-H4表达对抗肿瘤免疫有显著的不利影响 分析显示，被孕酮激活的孕激素受体（PR）会结合到B7-H4基因上游的-58 kb区域，该区域在女性生殖器官来源恶性肿瘤细胞和滋养层细胞中都相当活跃，具有显著的增强子特征，还可以与启动子区域直接发生相互作用，将该区域删除就能阻断孕酮处理对B7-H4表达的影响。此外，孕酮对B7-H4表达的影响还需要依赖表观遗传调控，关键的调节因子是组蛋白乙酰转移酶P300和“表观遗传阅读器”之一的溴结构域蛋白4（BRD4）。 孕酮结合到-58 kb增强子区域，是调控B7-H4表达的关键步骤 最后，研究者们评估了靶向B7-H4调节轴对免疫治疗的潜在影响：使用PR拮抗剂或BRD4降解剂来阻断孕酮对B7-H4表达水平的调节，都能够与PD-L1抑制剂实现协同增效，更好地抑制乳腺癌进展，对于存在B7-H4高表达的肿瘤，这套联合治疗方案或许是破解肿瘤微环境免疫抑制、改善疗效的全新选择，说不定就能攻破卵巢癌这样的免疫难治肿瘤呢。 参考文献： [1]Kareva I. Immune suppression in pregnancy and cancer: parallels and insights[J]. Translational Oncology, 2020, 13(7): 100759. [2]Yu J, Yan Y, Li S, et al. Progestogen-driven B7-H4 contributes to onco-fetal immune tolerance[J]. Cell, 2024. 本文作者丨谭硕

引言 免疫检查点阻断疗法（ICB）是治疗多种癌症的有效手段，但许多患者对现有免疫疗法反应不佳【1,2】。患者机体对肿瘤的免疫耐受由肿瘤微环境（TME）中复杂的免疫抑制网络所介导，是导致肿瘤免疫逃逸及对ICB抵抗的主要原因 【3,4】。鉴定新的免疫耐受机制有助于开发更有效的免疫疗法。与TME中有害的免疫耐受不同，妊娠期间母亲对胎儿的免疫耐受则对宿主有益，这为探索免疫耐受机制提供了理想的生理模型。一些关键的免疫抑制途径，如PD-L1、HLA-G、IDO、Treg等，在TME和母胎界面中均被激活并与癌症进展和母胎免疫耐受密切相关 【5-7】。B7-H4是属于B7家族的抑制性分子，在肿瘤免疫中扮演免疫检查点的角色【8-10】，但其在母胎免疫耐受中的作用尚不明确，且其表达受组织微环境中何种因素的调控亦有待进一步研究。 2024年7月4日，密歇根大学邹伟平教授团队（余家力博士和闫一剑博士为共同第一作者）在Cell上发表题为 Progestogen-driven B7-H4 contributes to onco-fetal immune tolerance 的研究论文，揭示免疫检查点分子B7-H4受孕激素调控并促进“癌-胚”免疫耐受的机制。 在该研究中，研究人员从免疫耐受微环境中的“非我”细胞类型（TME中的肿瘤细胞和母胎界面的滋养层细胞）入手，通过分析14个单细胞RNA测序（scRNA-seq）数据集， 发现B7-H4在TME中的肿瘤细胞和母胎界面中的滋养层细胞上均高度表达。值得注意的是，B7-H4在泛妇科癌症，如乳腺癌、卵巢癌、子宫内膜癌，中表达水平极高。作者在患者来源的组织切片标本中，验证了肿瘤细胞和滋养层细胞上B7-H4蛋白的表达。鉴于B7-H4介导免疫抑制的功能，这些结果提示B7-H4是一个潜在的“癌-胚”免疫耐受检查点。 为了探索B7-H4在母胎免疫耐受中是否发挥重要作用，研究人员利用B7-H4 基因敲除和野生型小鼠构建了妊娠模型。实验结果表明B7-H4的基因敲除在同种异基因的妊娠模型中会导致更多的胚胎吸收，并伴有母胎界面的免疫活化，但却并不影响同种同基因模型的妊娠结局。为了排除母体环境对实验结果的潜在影响，研究人员利用胚胎移植技术，将B7-H4-/-和WT两种基因型的胚胎移植入相同基因型的假孕雌鼠，结果同样表明B7-H4的缺陷会导致更多胚胎吸收。这些结果提示B7-H4的基因敲除导致的不良妊娠结局与免疫活化有关。作者进一步利用适应性免疫系统缺陷小鼠（RAG1-/-）和抗体清除实验证明CD8+ T细胞参与B7-H4介导的母胎免疫耐受。在终止妊娠的患者来源的母胎界面组织中，作者观察到表达B7-H4的滋养层细胞和CD8+ T细胞存在共定位，这提示B7-H4可能在人类的母胎免疫耐受过程中同样发挥作用。 B7-H4在母胎界面和泛妇科癌症中都高度表达，那么组织微环境中的何种因素在调控其表达呢？鉴于这两个不同微环境均受到女性激素的密切调控，研究人员进而发现孕激素可以显著上调乳腺癌以及滋养层细胞系中B7-H4的表达，而其它激素则没有这种效应。孕酮激活的孕激素受体（PR）会结合到 B7-H4 基因上游 -58 kb 处的区域，该区域具有增强子特征并与启动子区域直接相互作用。荧光素酶报告实验和基因敲除实验证明该-58 kb区域为调控B7-H4表达的增强子并介导孕激素调节B7-H4的功能。进一步研究表明，孕激素通过 PR-P300-BRD4 这一表观遗传调控轴来促进 B7-H4 表达。这一过程中，P300 作为组蛋白乙酰转移酶增强了增强子区域的活性，而 BRD4 作为表观遗传阅读器识别这些修饰并促进转录。 为了验证该分子通路是否调控肿瘤的免疫耐受，研究人员利用由MPA和DMBA（MPA为合成孕激素，DMBA为化学诱变剂，两者均为人乳腺癌的潜在风险因素）诱导的小鼠乳腺癌模型，发现合成孕激素MPA和 B7-H4 共同作用，促进小鼠乳腺癌的发生发展。进一步研究表明，肿瘤细胞表达的B7-H4 通过抑制 CD8+ T 细胞的活性，促进了肿瘤的免疫逃逸和生长。鉴于 B7-H4 在乳腺癌等多种癌症中高表达且当前批准的免疫疗法在这些癌症患者中效果有限，而靶向B7-H4的抗体药物尚处于临床试验阶段，于是研究人员利用上述乳腺癌模型来源的肿瘤细胞构建了同基因移植瘤模型，并尝试通过靶向孕激素介导的 B7-H4调控通路来解除B7-H4介导的免疫抑制、进而提高 ICB 的疗效。实验结果表明，使用 PR 拮抗剂或 BRD4 降解剂可以显著提高 靶向PD-L1的ICB 在 B7-H4 高表达的癌症模型中的治疗效果，这为癌症免疫治疗提供了新的策略。 综上所述，本研究发现B7-H4是介导“癌-胚”免疫耐受的检查点分子，揭示了其在癌症免疫耐受和母胎免疫耐受中均发挥的重要作用，深入阐述了孕激素诱导其受体结合到B7-H4基因上游的-58 kb增强子区域并招募P300-BRD4来调控B7-H4转录表达的新机制。最后，本研究提出了利用孕激素受体拮抗剂或者BRD4降解剂来增强B7-H4阳性癌症的免疫疗法的潜在治疗策略。 近期有研究表明雄激素调节抗肿瘤免疫并影响癌症的免疫治疗效果【11-13】。本研究则揭示了女性激素中的孕激素可通过调节免疫检查点分子B7-H4介导肿瘤和母胎免疫耐受，为内分泌系统和免疫系统的相互作用提供了一个新的范例。另外，临床研究表明孕激素类药物的使用与乳腺癌风险增高有一定相关性【14,15】，本研究从免疫学角度为该临床现象提供了一个可能的解释。 研究示意图(Credit: Cell) 参考文献 1. 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