作者: Gautier, Aurelie ; Woisetschlaeger, Maximilian ; Chinthrajah, R Sharon ; Eggel, Alexander ; Altman, Pablo ; Tassinari, Paolo ; Bottoli, Ivan ; Wood, Robert A

Food allergy (FA) is a growing healthcare problem worldwide and the rising prevalence in many countries can be attributed to lifestyle, environmental, and nutritional changes. Immunoglobulin E (IgE)-mediated FA is the most common form of FA affecting approximately 3%-10% of adults and 8% of children across the globe. Food allergen-induced immediate hypersensitivity reactions mediated by IgE and high-affinity IgE receptor (FcεRI) complexes on mast cells and basophils are a major hallmark of the disease. FA can affect several aspects of health-related quality of life and impose a substantial financial burden on patients and healthcare systems. Although currently there is one United States Food and Drug Administration (FDA) and European Medicines Agency (EMA)-approved treatment for peanut allergy (Palforzia), the main treatment approaches are based on allergen avoidance and symptom management. Thus, there is an urgent need for more effective and ideally disease-modifying strategies. Given the crucial role of IgE in FA, anti-IgE monoclonal antibodies are considered promising therapeutic agents. Talizumab was the first humanized anti-IgE antibody to demonstrate substantial protection against allergic reactions from accidental peanut exposure by substantially increasing the peanut reactivity threshold on oral food challenge. However, development of talizumab was discontinued and further trials were performed using omalizumab. In double-blind, Phase 2, placebo-controlled trials in patients with multi-FAs, sustained dosing with omalizumab, or omalizumab in combination with oral immunotherapy, enabled rapid desensitization to multiple trigger foods. In this review, we describe the development of ligelizumab (a derivative of talizumab), a next generation, humanized monoclonal anti-IgE antibody, its existing clinical evidence, and its potential in the management of FA. When compared with omalizumab, ligelizumab binds with ∼88-fold higher affinity for human IgE and recognizes a different epitope that substantially overlaps with the binding site of FcεRI. These properties translate into a high potency to block IgE/FcεRI signaling in both in vitro and in vivo studies. Given its efficient suppression of IgE levels, good safety and pharmacokinetic/pharmacodynamic profile, ligelizumab clearly warrants further studies for the potential management of FA.

2022-09-01·Clinical and translational allergy

Systematic review of monotherapy with biologicals for children and adults with IgE‐mediated food allergy

Article

作者: Muraro, Antonella ; Alvaro Lozano, Montserrat ; Zuberbier, Torsten ; Arasi, Stefania ; Roberts, Graham ; Ebisawa, Motohiro ; Silva, Debra de ; Singh, Chris

Abstract:

Background:

Biological therapies relieve symptoms in allergic inflammatory diseases so we systematically reviewed the evidence about whether biological monotherapy could benefit people with IgE‐mediated food allergy.

Methods:

We searched six bibliographic databases from 1946 to 30 September 2021 for randomised and non‐randomised controlled trials about biological monotherapy in people with IgE‐mediated food allergy confirmed by oral food challenge. We used the Grading of Recommendations, Assessment, Development and Evaluation approach to narratively summarise findings from three trials with 118 participants. The studies were too heterogeneous and sparse to conduct meta‐analysis.

Results:

We included one randomised trial about etokimab, one about omalizumab and one about the discontinued TNX‐901. All were in people with peanut allergy in the USA, mostly aged 13+ years. There was a trend towards improved tolerance of peanut during treatment, with few side effects. However, we have very low certainty about the evidence due to the small number of trials and participants. No included trial reported on quality of life or cost‐effectiveness.

Conclusions:

There is not yet enough certainty to support offering etokimab or omalizumab widely for food allergy. Clinicians may consider the merits for individuals, but large randomised trials with standardised measures are needed to confirm the safety, efficacy and most suitable candidates, doses and durations of treatment before more universal use.

2004-01-01·Novartis Foundation symposium

New approaches for the treatment of anaphylaxis.

Article

作者: Sampson, Hugh A ; Leung, Donald Y M ; Li, Xiu-Min ; Shanahan, William R

Anaphylaxis represents the most extreme form of life-threatening allergic reactions. However, effective long-term therapies for this condition are not currently available. A number of potential approaches have proven effective in murine models of peanut-induced anaphylaxis and are currently being considered in humans, including the use of vaccines containing 'engineered' recombinant food proteins and Chinese herbal medications. TNX-901 is a humanized IgG1 anti-IgE mAb that recognizes and masks an epitope in the CH3 region responsible for binding to the high affinity Fc epsilon receptor (FcepsilonRI) on basophils and mast cells. Recently, we conducted a double-blinded, placebo-controlled, randomized, dose escalation trial in 84 patients with a history of peanut allergy. Allergy was confirmed and the threshold dose of encapsulated peanut established by a double-blinded, placebo-controlled oral food challenge (DBPCOFC) at screening. Patients were randomized 3:1 in three dose groups to receive either TNX-901 (150, 300 and 450 mg) or placebo subcutaneously every four weeks for four doses. They underwent a final open food challenge within 2-4 weeks after the last dose of study medication. From mean baseline values of 178-436 mg in the various treatment groups, the mean increases in the open food challenge threshold were 710, 913, 1650 and 2627 mg for the placebo, 150, 300 and 450 mg for TNX-901 dose groups, respectively (P = 0.0004, 450 mg vs. placebo; P = 0.0008 for trend with dose). TNX-901 was well tolerated. TNX-901 at a dosage of 450 mg significantly increased the threshold of sensitivity to peanut by open food challenge from a level of about half a peanut (178 mg) to almost nine peanuts (2805 mg). These studies suggest that treatment of patients with anti-IgE therapy may represent an effective long-term approach for management of food-induced anaphylaxis.

项与 Talizumab 相关的新闻（医药）

2021-01-17

·佰傲谷BioValley

结束20余年备胎生涯---诺华奥马珠单抗重磅接班人Ligelizumab现身台前

近日（2020年1月14日），诺华宣布其新一代IgE抗体ligelizumab（QGE031）获得FDA授予的突破性疗法认定，用于治疗慢性自发性荨麻疹(CSU)。命运弄药 Ligelizumab(QGE031)是靶向Ig E的全人源IgG1k单抗，与奥马珠单抗同为第一代IgE抗体。 ligelizumab最初由Tanox开发。 1987年，Tanox利用其专业技术平台开发出了抗IgE的多个候选单抗，CGP51901便是候选分子之一。 1989年，Tanox与Genentech就CGP51901的合作开发进行了一次洽谈，在后者承诺不会盗用任何专有信息后，Tano向Genentech透露了 CGP51901 的相关技术细节。 1990年双方合作谈判失败。几乎在同一时期，基因泰克宣称也开发出了一款IgE抗体，也就是后来大名鼎鼎的奥马珠单抗（研发代号：rhuMAb-E25），巧合的是，rhuMAb-E25的抗原结合特异性等数据与CGP51901非常相似。同年， Tanox与Ciba-Geigy（ 1996年，Ciba-Geig被合并入诺华旗下的Sando z ）达成合作，双方共同开发CGP51901。注：奥马珠单抗(Xolair)一进入市场就给两家公司带来了非常可观的收入，是年销售额超30亿美元的款重磅炸弹药。2003年，奥马珠单抗首次获FDA批准用于治疗过敏性哮喘。2014年再次获批用于治疗慢性特发性荨麻疹。2020年，获批用于治疗鼻内给药皮质类固醇响应不足的成人鼻息肉。 1991年，CGP51901获FDA批准进入临床试验。 1993年，Tanox公司向Genentech提起了诉讼，指控其违反合同、保密协议以及不公平的商业行为。双方围绕专利问题陷入了长达3年的法律纠纷。直到1996年，三方达成庭外和解，协议共同开发IgE抗体。彼时，rhuMAb-E25因为生产能力更加优，被选择进行后续开发。而TNX-901的开发因陷入法律争端，Tanox被裁定不能继续开发，这一搁置就是20年之久。注：2007年8月基因泰克以9.19亿美元现金收购了Tanox。2009年3月，Genentech又被罗氏收购。击败Xolair 为了应对Xolair面临的专利悬崖挑战（ Xolair的一项关键专利已于2018年到期，而其他的注射配方专利分别在2021、2024年到期）。2018年， TNX-901得到了诺华的重点开发。在TNX-901的基础上，诺华进行了亲和力改造(更名为Ligelizumab)。据诺华称，Ligelizumab的亲和力大约为Xolair的50倍，两者间对IgE的识别和结合表位存在差异，经亲和力改造的ligelizumab对IgE/FcεRI信号传导阻滞明显增强。在得到充分的开发机会后，Ligelizumab就显示出了它的不简单。在此前开展的一项治疗CSU的头对头IIb期临床研究中，Ligelizumab一举击败了Xolair。此研究结果显示，在第12周，与接受奥马珠单抗/安慰剂治疗的患者相比，72mg ligelizumab治疗组中实现CSU症状的完全控制的患者显著更多。目前，ligelizumab已经进入CSUd的III期临床开发阶段，用于经H1-抗组胺药疗效不佳的CSU患者治疗。诺华已表示计划今年底向FDA提交上市申请。 Xolair之后事实上，靶向IgE抗体药物开发并不顺利，奥马珠单抗依然是唯一获批上市的靶向结合并阻断IgE的抗体药物。从目前已公布临床数据的在研产品来看，除了Ligelizumab外，目前还未有其他候选人能超越奥马珠单抗。 Quilizumab Quilizumab（FB825）是Genentech开发的第二代IgE抗体,可靶向细胞膜IgE上的CεmX片段。去年4月，它被Genentech以5.3美元总额转让给丹麦利奥制药。在过敏性鼻炎中开展的Ⅰ期临床研究及过敏性哮喘的 Ⅱ期临床研究中，Quilizumab显示出降低了30%-40%的血清中游离IgE，不过，后续的临床研究中却未显示出对临床结果的改善。 MDI4212 MDI4212的是MedImmune开发了同时中和IgE和通过ADCC清除mIgE-B细胞的抗体（MDI4212）。MDI4212可以阻断IgE结合FcεRIα，通过空间位阻等机制，阻断IgE和CD23的结合。2013年开展了Ⅰ期临床，不过临床疗效不及奥马珠单抗，之后一直没有进一步的临床试验。 XmAb7195 XmAb7195是奥马珠单抗小鼠母本抗体（MaE11）人源化亲和力成熟，Fc段和抑制性受体FcγRIIb亲和力增强的抗体。通过将B细胞表面FcγRIIb和mIgE聚集，降低IgE的产生。临床Ⅰb期于2017年已经完成，但至今未尚未公布结果，估计也比较悬。除了针对IgE靶点的创新药开发之外，随着奥马珠单抗专利的陆续到期，其仿制药也开始兴起，目前迈博药业（CMAB007）、Sorrento（STI‐004）的奥马珠单抗生物类似药已进入临床III期。不过，都还尚未提出上市申请。 Ligelizumab凭借优异的临床疗效，终于走到了台前。而作为备胎角色，Ligelizumab也确然发挥到它的作用，以及时应对奥马珠单抗专利陆续失效的现状，帮助诺华稳固在CSU治疗领域的地位。参考出处 1.https://doi.org/10.1111/all.14308 2.https://endpts.com/novartis-gets-breakthrough-designation-for-xolair-successor-setting-up-spotlight-for-phiii-readout-later-this-year/ 版权声明：本文转自医药合作投融资联盟，如不希望被转载的媒体或个人可与我们联系，我们将立即删除【关于药融圈】药融圈围绕我国生物医药产业链，针对生物医药大数据、技术和资本投资、药融园(产业园)等开展系列系统性工作，促进我国生物医药产业健康发展，完善产业链，共同面对全球合作和竞争。点分享点点赞点在看