Immunomodulatory ADCs: A New Weapon Against Autoimmune Diseases

▎This article is contributed by Ying’en Biotech (slightly edited)

Since the first antibody-drug conjugate (ADC) was approved for the treatment of acute myeloid leukemia in 2000, after more than twenty years of exploration and development, 14 ADC drugs have been successfully approved for clinical treatment of tumors. In August 2022, the FDA announced the accelerated approval of the ADC Enhertu, jointly developed by AstraZeneca and Daiichi Sankyo, making it the first HER2-targeted therapy for patients with HER2 low-expressing metastatic breast cancer, further confirming the excellent efficacy of ADC drugs in tumor treatment.

We can’t help but ask, can this emerging treatment method, ADC, also benefit patients with autoimmune diseases in non-tumor fields?

▲History of ADC Development (Screenshot source: Reference [1])

Pathogenesis and Treatment Status of Autoimmune Diseases

The immune system is a regulatory mechanism evolved to resist external material invasion and maintain internal homeostasis. It achieves its specific regulatory functions through the synergistic action of immune cells and effector factors. However, an imbalance in the body’s regulation can lead to the loss of immune tolerance and the occurrence of autoimmune diseases. Autoimmune diseases are characterized by abnormal immune responses, either locally or systemically, and include rheumatoid arthritis (RA), ankylosing spondylitis (AS), juvenile idiopathic arthritis (JIA), non-radiographic axial spondyloarthritis (nr-AxSpA), psoriasis, psoriatic arthritis (PsA), Crohn’s disease (CD), ulcerative colitis (UC), systemic lupus erythematosus (SLE), lupus nephritis (LN), multiple sclerosis (MS), bronchial asthma, and more.

As a major class of diseases that threaten human health and quality of life, autoimmune diseases affect 5% to 10% of the world’s population. However, the existing treatment options for this large class of nearly 200 diseases are quite limited.

Among them, glucocorticoids are a basic treatment option with broad-spectrum anti-inflammatory, immunosuppressive, anti-toxic, and anti-shock effects, and are widely used in the treatment of various autoimmune diseases. However, the adverse reactions associated with these products are often difficult to avoid. High doses or prolonged use of glucocorticoids can suppress the immune system, leading to bacterial, fungal, or viral infections; can raise blood pressure and blood sugar, causing chronic hypertension and diabetes; can cause metabolic disorders, leading to centripetal obesity (commonly known as “moon face” or “buffalo hump”); can raise intraocular pressure, causing glaucoma; and can promote gastric acid secretion, leading to gastric ulcers.

In recent years, the emergence of targeted agents has provided more treatment options for patients with autoimmune diseases. The pathogenesis of autoimmune diseases is complex, involving the abnormal activation of immune cells, inflammatory cytokines, and intracellular signaling molecules. Although the pathophysiological mechanisms differ among various autoimmune diseases, several common inflammatory factors utilize the same signaling pathways. Therefore, there has been a trend towards targeting these immune therapy targets through small molecules or biological agents to treat autoimmune diseases.

Small molecule targeted therapy drugs represented by JAK pathway inhibitors (JAKi) achieve immunosuppressive effects by inhibiting cytokine signaling pathways. Overactive immune cells secrete inflammatory factors, which transduce inflammatory signals by binding to their homologous receptors. Once bound to inflammatory cytokines, the receptors activate JAK family proteins to induce the phosphorylation, dimerization, and nuclear translocation of STATs, promoting gene transcription that facilitates cell proliferation and differentiation, as well as the production of various inflammatory mediators, further exacerbating autoimmune inflammation. JAK inhibitors have demonstrated good therapeutic effects on various autoimmune diseases and are widely used in the treatment of rheumatoid arthritis and other diseases. However, despite avoiding the systemic side effects of glucocorticoids, their broad immunosuppressive effects increase the risk of infections and carcinogenesis.

Biological targeted therapy drugs, especially the emergence of antibody drugs, have brought new avenues for the treatment of immune diseases. Antibodies possess the precision of highly specific target recognition and the long half-life, providing them with advantages that small molecules cannot match. Humira (adalimumab) is a successful representative of antibody drugs, having topped global drug sales for several consecutive years. Due to the complex pathogenic mechanisms of most autoimmune diseases, which are not caused by a single factor, the precise characteristic of antibody drugs targeting a single target also becomes a limitation in their inability to broadly suppress multiple pathogenic factors. The efficacy of treating autoimmune diseases with single antibody drugs is often limited, requiring collaboration with small molecule drugs, and long-term treatment can lead to drug tolerance.

In addition, a significant portion of autoimmune diseases still lacks approved therapeutic drugs. Therefore, both research institutions and major pharmaceutical companies are searching for more efficient, safe, and low-toxicity treatment methods for autoimmune diseases.

Can Immunomodulatory ADCs Become a New Weapon?

Faced with the substantial unmet clinical needs of autoimmune diseases, can ADCs make a difference? Research shows that the majority of autoimmune diseases arise from an imbalance in the activation and suppression of the immune system, leading to damage to the body’s tissues and organs caused by overactive immune cells or overexpressed inflammatory factors. Therefore, helping patients regain immune balance is key to treatment. Immunomodulatory ADCs can suppress excessive immune activation on one hand while avoiding systemic immunosuppression on the other, thus achieving precise regulation of immune balance, and are expected to become more efficient, safe, and low-toxicity treatment methods for autoimmune diseases.

Looking back at the development history of ADCs in cancer treatment, the advancement of ADC technology has made it possible to use antibody-conjugated small molecule drugs for the treatment of autoimmune diseases. In the initial development phase of ADCs, the instability of linkers resulted in the effective payload (payload) being released in non-tumor environments, leading to hematotoxicity and other side effects. With advancements in conjugation technology, the use of more stable linkers significantly enhances drug stability in peripheral areas and reduces non-target toxicity. Furthermore, the development of antibody drugs has evolved from chimeric antibodies, humanized antibodies to fully human antibodies, which not only improves the specificity of antibody drugs and enhances their biological functions but also significantly reduces immunogenicity. These developments provide the necessary technical foundation for enhancing safety, reducing side effects, and long-term use.

Similar to anti-tumor ADC drugs, immunomodulatory ADCs can achieve precise drug delivery through the antibody portion binding to the target, thereby reducing the side effects of the effective payload on normal organs that are not targeted. Unlike the single delivery function of the antibodies in anti-tumor ADC drugs, the antibody portion of immunomodulatory ADCs not only performs targeted delivery but also has therapeutic effects that regulate the disease at the target. Additionally, unlike the anti-tumor ADCs that target and kill malignant cells, the effective payload of immunomodulatory ADCs requires precise regulation of the immune system, thus the effective payload has not only high efficacy but also many requirements (see the section “Research Ideas for the New Generation of Immunomodulatory ADCs”).

Existing studies have shown that conjugating glucocorticoid drugs to therapeutic antibodies to obtain immune ADCs can precisely exert the effects of both antibodies and glucocorticoid drugs, providing new avenues for the treatment of autoimmune diseases. Immunomodulatory ADCs can complement each other, leveraging the blocking and regulatory functions of antibody drugs while utilizing the highly specific targeting recognition functions of antibodies to deliver glucocorticoids to the effector cells that need regulation. Target-mediated endocytosis further delivers the ADC into the cell interior, releasing the glucocorticoid effective payload to achieve extensive regulation of cell signaling and transcription at the site of inflammation.

Based on this concept, AbbVie has developed immuno ADC molecules ABBV-154 and ABBV-3373, which conjugate TNFα antibodies with glucocorticoids based on adalimumab (Humira). As a new generation of TNFα-targeting therapeutic drugs, these ADCs have shown better therapeutic effects in preclinical animal models compared to antibody therapy. Compared to glucocorticoid treatment, they exhibited smaller changes in the bone injury marker P1NP in acute hypersensitivity models and lower endocrine impacts on the hypothalamic-pituitary-adrenal axis. Currently, research on these two products for indications such as rheumatoid arthritis, polymyalgia rheumatica, and Crohn’s disease has progressed to phase 2 clinical trials.

In the phase 2 clinical trial M16-560 for rheumatoid arthritis, ABBV-3373 effectively reduced disease activity compared to Humira, without showing systemic glucocorticoid effects. Statistical comparisons showed a greater change in the primary endpoint DAS28-CRP from baseline to week 12 in the ABBV-3373 treatment group compared to the pre-specified historical average of adalimumab (-2.13) (-2.65, p=0.022). Furthermore, the probability of achieving a greater improvement in DAS28-CRP from baseline to week 12 with ABBV-3373 compared to historical data of adalimumab was 90%. Additionally, assessments of serum cortisol levels during the 12-week treatment period indicated that ABBV-3373 did not exhibit systemic glucocorticoid effects. In the trial, the overall incidence of adverse events (AEs) for ABBV-3373 was lower than that of adalimumab (35% [n=11] vs 71% [n=12]). This clinical trial result strongly supports the feasibility of developing immune ADCs for autoimmune diseases.

Research Ideas for the New Generation of Immunomodulatory ADCs

Looking back at history, the concept of immunomodulatory ADCs has been preliminarily validated; moving forward, there are still challenges in developing the next generation of immunomodulatory ADCs. For example: How to select effective payloads that are efficient, safe, and durable to enhance the efficacy of immune ADCs and reduce side effects? How to choose appropriate targets and antibodies for indications? How to efficiently complete the CMC and clinical development of immune ADC drugs?

At multiple industry conferences in 2022, Ying’en Biotech introduced its development ideas for the new generation of DIMAC immunomodulatory ADCs.

In terms of effective payload design, firstly, due to the precise targeting characteristics of ADC drugs, the effective payload must be more active than traditional glucocorticoid small molecules; secondly, due to the low frequency of ADC drug administration, the effective payload must have long-lasting effects, with a duration of action on glucocorticoid receptors longer than that of traditional glucocorticoid small molecules; finally, to minimize the systemic side effects of glucocorticoids on other organs, the effective payload must have a mechanism for rapid clearance from the human body.

In terms of target and antibody selection, it is required that the target itself plays a driving role in the onset and development of autoimmune diseases, while the antibody needs to have high target selectivity as well as the ability to regulate the target’s function and therapeutic effects on autoimmune diseases.

Standing on the wave of new generation ADC technology platforms, Dr. Zhu Zhongyuan of Ying’en Biotech stated: “To let ADC technology shine in autoimmune diseases, we must not only continuously refine the new generation of ADC technology based on existing technological foundations and expand its application scope, but also adhere to the spirit of ‘acting fast alone, going far together’, strengthening cooperation with excellent CRO/CDMO companies in the industry, sharing resources, and establishing a more comprehensive ADC drug research and development ecosystem.”

References:

[1] Fu, Z., Li, S., Han, S. et al. Antibody drug conjugate: the “biological missile” for targeted cancer therapy. Sig Transduct Target Ther 7, 93 (2022). https://doi.org/10.1038/s41392-022-00947-7

[2] Goess C A , Stoffel R H , Li X , et al. Design and Development of Glucocorticoid Receptor Modulators as Immunology Antibody–Drug Conjugate Payloads[J]. Journal of Medicinal Chemistry, 2022(65-6).

This article is from Ying’en Biotech, and Yi Yao Guan Lan has obtained authorization for publication from Ying’en Biotech.

Disclaimer: The content team of WuXi AppTec focuses on introducing global biomedical health research progress. This article is for informational exchange purposes only, and the views expressed do not represent the position of WuXi AppTec, nor do they represent WuXi AppTec’s support or opposition to the views expressed. This article is not a treatment recommendation. For treatment guidance, please visit a formal hospital.

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