在人類免疫系統的複雜網絡中，自體抗體是一類能深刻影響疾病發展的關鍵因子。我們的研究聚焦於免疫失調與感染疾病，特別是那些由抗細胞激素自體抗體所驅動的疾病。這些研究不僅揭示了許多過去難以解釋的感染是由於抗細胞激素自體抗體所造成的，為臨床診斷與治療策略的開發奠定基礎，更成為藥物開發的一條特別的路。

抗伽瑪干擾素自體抗體疾病（anti-IFN-g autoantibodies, AIGA）與成人感染重症伽瑪干擾素是T細胞與自然殺手細胞產生，具有強力免疫活化能力的細胞激素。一旦伽瑪干擾素的功能喪失，會導致宿主對分枝桿菌與其他胞內病原的抵抗能力顯著下降，甚至導致死亡。過去的研究發現，在難以解釋的嚴重分枝桿菌感染成人病人中，可以找到抗伽瑪干擾素自體抗體解釋這樣的免疫缺失與感染，使得抗伽瑪干擾素或其他後來發現的抗細胞激素的自體抗體，被認為是一種新的免疫缺失的機制與病因。我們實驗室研究發現，這種疾病在東亞地區，尤其是台灣，具有高度盛行率，而且是因為與與這地區族群有特有特定人類白血球抗原基因型（HLA, DRB1*16:02與15:02）密切相關，說明了其族群與地理分布的特殊性。這類研究成果，不僅改變了過去對「僅侷限於先天缺陷的免疫缺損」的理解，也使抗伽瑪干擾素自體抗體疾病成為首個與人類白血球抗原相關、由自體抗體引起的後天免疫缺陷疾病，並提供一套完整的臨床與分子診斷依據。

分子模擬機制與創新干擾素設計

進一步的抗體特性分析揭示，病人可能因接觸環境中的麴菌而產生針對其蛋白質的免疫反應，這些蛋白質片段與人類伽瑪干擾素的序列相似，進而誘發交叉反應並產生自體抗體。此「分子模擬（molecular mimicry）」理論，為自體抗體產生的成因提供了重要線索。根據這一機制，團隊設計了去除免疫攻擊位點的改良型伽瑪干擾素（epitope-erased IFN-g），證實其在體外能避開自體抗體中和，並恢復訊號傳導功能。這項成果發表於頂級期刊自然醫學《Nature Medicine》，並獲該期專文評論，成為疾病機制導向治療開發的範例。 

高親和力中和性抗體的功能與藥物潛力

在技術上，研究團隊建立了具挑戰性的自體抗體單株分離平台，成功分離出多株高親和力的抗伽瑪干擾素抗體。這些抗體的功能經單分子影像技術驗證，發現其主要是阻斷伽瑪干擾素受體的組裝過程，而非單純干擾配體與受體的結合，為免疫訊號中斷的機制提供了新見解。這類功能性分析進一步強化了其作為潛在治療工具的可行性。另外一方面，這樣從病人分離的抗體，是全人類來源的抗體，且具有高親和性與生理活性，及具有開發成為藥物，治療那些伽瑪干擾素過多造成的疾病。 

對抗白斑症的利器

伽瑪干擾素有強力免疫活化的作用，而然過度分泌會造成免疫系統過度激化，造成嚴重的發炎問題，甚至導致死亡。例如感染造成的過度伽瑪干擾素分泌，會造成嗜血性細胞綜合症，這是一個極高死亡率的疾病。另一種狀況下，伽瑪干擾素在皮膚中過度作用，會導致黑色素細胞死亡，病人會因此缺乏黑色素而導致白斑症。白斑症雖然不致命，但是對病人的心理跟社交上造成嚴重的影響，目前缺乏長期且副作用小的有效治療方式，只能以副作用大的如類固醇等治療，急需有效的治療方式。學理上，抗伽瑪干擾素抗體，在適當的劑量下，可以中和這些過多的干擾素，阻止黑色素細胞死亡。

實驗室的研究成果，已經技轉給台灣本土生技公司”安立璽榮”稱作Indemakitug，經過嚴謹的製程開發，目前已經完成臨床一期試驗，顯示出高安全性，並獲得科技部傑出技轉獎與台北市生技獎的肯定。安立璽榮獲得國內各重要創投基金的支持，即將開始臨床二期試驗驗證對白斑症的治療效果，是一個台灣產學合作攻克創新抗體藥物的重要發展。當然這個藥物也具有治療其他伽瑪干擾素過度活化疾病的潛力，未來應有更多的適應症開發的價值，值得期待。

（113年TBF吳火獅醫學獎、長庚大學分子及臨床免疫中心　顧正崙特聘教授）

Autoantibodies in Immune Dysregulation and Infectious Diseases: Mechanisms and Therapeutic Implications 

Autoantibodies represent critical modulators within the complex network of the human immune system, profoundly influencing disease pathogenesis. Our research focuses on immune dysregulation and infection, particularly diseases driven by anti-cytokine autoantibodies. These studies have elucidated that many previously unexplained infections are attributable to neutralizing anti-cytokine autoantibodies, providing a foundation for novel diagnostic strategies, therapeutic development, and mechanistic drug discovery.

Anti–IFN-γ Autoantibody Syndrome and Adult-Onset Severe Infections
Interferon-gamma (IFN-γ), produced by T cells and natural killer cells, is a key cytokine in host defense against intracellular pathogens. Loss of IFN-γ activity results in profound susceptibility to mycobacteria and related organisms, often leading to fatal infections. Our work and that of others have established that neutralizing anti–IFN-γ autoantibodies underlie cases of adult-onset disseminated nontuberculous mycobacterial infections, redefining the landscape of acquired immunodeficiency.We identified a high prevalence of this syndrome in East Asian populations, particularly in Taiwan, with a strong genetic association with specific HLA alleles (DRB116:02 and DRB115:02). These findings delineate a population-specific acquired immune defect linked to autoimmunity and human leukocyte antigen polymorphisms, challenging the previous dogma that immune deficiencies are confined to congenital etiologies.

 

Molecular Mimicry and the Development of Epitope-Escaped IFN-γ
Characterization of patient-derived autoantibodies revealed that environmental exposure to mold-derived proteins may trigger autoimmunity via molecular mimicry, owing to sequence homology with human IFN-γ. Leveraging this mechanistic insight, we engineered an "epitope-erased" variant of IFN-γ that selectively removes immunogenic epitopes while preserving biological activity. This modified cytokine successfully evades neutralization by patient autoantibodies and restores downstream signaling in vitro. These findings, published in Nature Medicine and highlighted by editorial commentary, exemplify a mechanistic approach to the design of immune-escape biologics.

Isolation of High-Affinity Neutralizing Autoantibodies and Therapeutic Potential
We developed a robust platform to isolate monoclonal autoantibodies directly from patients, recovering multiple high-affinity clones. Single-molecule imaging and functional assays revealed that these antibodies predominantly inhibit receptor complex assembly rather than simple ligand-receptor binding. This novel insight into IFN-γ signal blockade highlights their utility as therapeutic tools. These fully human, physiologically active antibodies possess strong potential for therapeutic development, not only as models of pathological autoimmunity but also as candidate biologics for diseases characterized by IFN-γ overactivity.

Therapeutic Application in Vitiligo and Beyond
Dysregulated IFN-γ activity contributes to various hyperinflammatory conditions, including hemophagocytic lymphohistiocytosis and autoimmune skin disorders such as vitiligo. Although non-lethal, vitiligo significantly impacts patients' psychosocial well-being and currently lacks safe, long-term effective therapies. Preclinical data demonstrate that controlled administration of anti–IFN-γ antibodies can neutralize excess cytokine activity and prevent melanocyte loss. 

Our lead therapeutic candidate had been licensed to the biotech company “Elixiron Immunotherapeutic. The candidate, Indemakitug, has completed Phase I clinical evaluation with favorable safety outcomes. The program has been recognized with multiple awards for excellence in technology transfer and is advancing to Phase II clinical trials to assess efficacy in vitiligo. Given the central role of IFN-γ in diverse inflammatory disorders, Indemakitug and related molecules hold promise for broader therapeutic indications.

(2024 TBF Wo Ho-Su Medical Award, Distinguished Professor Cheng-Lung Ku)