Lu knows horsepower and explores the truth about the secondary failure of biologics

*Only for medical professionals to read for reference.
From the perspective of immunogenicity, how does the treatment of ankylosing spondylitis in the marathon match the treatment plan? The advent of the era of biological agents makes us extremely excited and delighted.

In the past, diseases that were difficult to effectively treat, especially complex autoimmune diseases such as ankylosing spondylitis (AS), have been effectively controlled and significantly improved under the treatment of biological agents.

However, the use of biological agents is not permanent.
Many patients and doctors have had the experience that biological agents that have achieved good efficacy in the early stage show a trend of diminishing efficacy over time.

This in the end is why? How to prevent and deal with such phenomena in clinical practice? Today, we will discuss the immunogenicity of biological agents, the occurrence of anti-drug antibodies (ADAs) and clinical countermeasures, and invite Professor Wang Caihong from the Second Hospital of Shanxi Medical University to comment for us.

1 "Immunogenicity"-a key factor hindering the long-term efficacy and safety of biological agents.
Existing biological agents are mainly antibody drugs.
These macromolecular antibody drugs, as foreign proteins, inevitably become Cause the body's own immune response, thereby inducing the production of ADAs.

The immunogenicity of a biological agent refers to its ability to induce the production of ADAs.

ADAs can be produced through T cell dependent (Td) and T cell independent (Ti) pathways.

In the Td pathway, the participation of T cells is a necessary condition for the activation of B cells and the production of ADAs; while in the Ti pathway, exogenous proteins can directly activate B cells through B cell receptors (BCR) to produce ADAs.

However, the ADAs produced by the two pathways are different.
The antibodies produced by the Ti pathway are relatively limited in isotype and affinity, and have a shorter life span; the antibodies produced by the Td pathway have higher affinity and can trigger Stronger and longer lasting antibody response.Therefore, most of the sustained, non-neutralizing ADAs induced by biological agents are produced through the Td immune pathway, and the production of these ADAs has a large and profound impact on the pharmacological activity and clinical efficacy [1-2].

Figure 1: The immunological process of the formation of ADAs (Td and Ti pathways).
Since all biological agents have the ability to induce the body's immune response, they may have varying degrees of immunogenicity.

Through the formation of immune complexes, ADAs can neutralize or change the clearance of biological agents, reduce the efficacy of drugs or bring adverse reactions [3-4].

From mild transient antibody reactions to loss of clinical efficacy and life-threatening reactions, the immunogenicity of biologics is closely related to clinical treatment outcomes (Figure 2) [5].

Figure 2: The immunogenicity of biological agents affects the clinical outcome.
Back to the question raised at the beginning of this article, why do patients have good initial efficacy after using certain biological agents, but after a certain period of time, they can’t get continuous improvement or relapse? In fact, this phenomenon is clinically called secondary failure, and the generation of ADAs is the main reason for the secondary failure of biological agents.

Adjusting the medication strategy or even stopping the medication due to secondary failure is not conducive to the long-term treatment and management of patients with chronic diseases such as AS.

Therefore, the occurrence of immunogenicity of biological agents should arouse our extensive attention and attention.

2 What factors affect the occurrence of ADAs? How to evaluate the immunogenicity of different biological agents? Although all biological agents have immunogenic risks and may induce the production of ADAs.

However, due to many factors, the probability of ADAs in the patient's body is different.

The factors affecting the immunogenicity of biological agents can be divided into the following three categories [5-6]: drug-related factors, including drug targets, drug molecular weight and structural characteristics, preparation technology, degree of humanization, etc.
; treatment-related factors: Dosage amount and frequency, route of administration, whether to combine medication, etc.
; patient-related factors: patient immune status, genetic susceptibility, age and disease state, etc.

Among them, drug-related factors are the most researched factors in the field of biological preparations, especially the impact of humanization on immunogenicity.

It turns out that the higher the degree of humanization of the antibody, the lower the immunogenicity (Figure 3).

Among the four types of monoclonal antibodies, fully human monoclonal antibodies have the lowest immunogenicity, which plays an important role in reducing the production of ADAs, improving efficacy and safety [7-8].

Figure 3: The average immunogenicity of different types of monoclonal antibodies.
In order to reasonably avoid or control the potential risks and negative effects brought about by the immunogenicity of biological agents, they should be evaluated and screened in the development stage and clinical application stage.

So, how to evaluate the immunogenicity of different biological agents? Under normal circumstances, the detection, quantification and description of ADAs are important steps in assessing immunogenicity [5].

In a predictive sense, the evaluation results of non-clinical animal models cannot accurately infer the human situation.

Animals are occasionally immunogenic, but humans are highly immunogenic, and animals are highly immunogenic but humans are low immunogenic.

Therefore, its predictive value is low [5].

The immunogenicity data of clinical trials can provide us with more reliable supporting data.

Common methods for detecting ADAs include enzyme-linked immunosorbent assay (ELISA), radioimmunoprecipitation assay (RIA/RIPA), fluorescence activated cell sorting (FACS), high performance liquid chromatography (HPLC), etc.
[5].

By evaluating and comparing the incidence of ADA (TE-ADA) in patients after treatment*, we can learn about the immunogenicity of different biological agents, so as to better use biological agents in treatment.

Note: *TE-ADA= Percentage of patients who were negative at baseline becoming ADA positive (%) 3 Explore the immunogenicity of biological agents used for AS treatment.
Currently, biological agents used for AS treatment mainly include tumor necrosis factor-α ( TNF-α) inhibitors and IL-17A inhibitors, such as adalimumab, golimumab, infliximab (TNF-α inhibitor), and skukuzumab (IL-17A inhibitor) ( Figure 4). Figure 4: Monoclonal antibodies used to treat AS (*iditizumab has not yet been approved for AS indications in China) 1TNF-α inhibitors The incidence of ADAs is different for different TNF-α inhibitors.

A meta-analysis study showed that the average incidence of ADAs for TNF-α inhibitors was 12.
7%, while the incidence of ADAs for adalimumab and golimumab, which are also fully human monoclonal antibodies, was 14.
1% and 3.
8%, respectively , Compared with human-mouse chimeric infliximab [9].

Figure 5: The incidence of ADAs of different TNF-α inhibitors in the meta-analysis.
Among patients with spondyloarthritis (SpA) who use TNF-α inhibitors to develop ADAs, there is an 82% chance of reducing their clinical response (Figure 6) 9], and is associated with an increase in adverse events [10], leading to an increase in the incidence of treatment failure and interruption (Figure 7) [11].

Figure 6: The possibility that the presence of ADAs leads to a decrease in the clinical response of patients with various diseases to TNF-α inhibitors Figure 7: The presence of ADAs can lead to an increase in the incidence of treatment failure or interruption 2IL-17A inhibitors are both IL-17A inhibition What's the difference in immunogenicity between scocilizumab and ezizumab? Since the immunogenicity depends on the T cell immune mechanism, the researchers evaluated their ability to induce drug-resistant T cell responses in vitro and their potential to produce ADAs.

They found that in the cell culture medium of healthy donors, the T cell response frequency of skucilizumab was significantly lower than that of ecchizumab.
Compared with ecchizumab, the response rate of the skucilizumab donor was *Low, the number of pre-existing T cells and the number of specific CD4 T cells† is significantly less (Figure 8 and Figure 9) [12-13].

Note: *Response rate=number of healthy donors that produce monoclonal antibody-specific T cells/total number of healthy donors*100% (the higher the response rate, the higher the probability that the human body will respond to antibodies with T cells.
Antibodies are used The higher the possibility of producing anti-drug antibodies during treatment).

†Antibodies act on healthy donor monocytes to produce specific CD4+ T cells.
The larger the number of cells, the more T cells are induced by the therapeutic antibody, and the greater the possibility of producing anti-drug antibodies when the antibody is used for therapy.
. Figure 8: Recchiuzumab has the lowest donor response rate and the least number of T cells.
Figure 9: Compared with ixizumab, the number of cucuzumab-specific CD4+ T cells is significantly reduced.
In addition, there are studies on the treasurer The specific T cell epitopes (ie epitopes recognized by T cell receptors) of Chiyuumab and Chiyuumab were tested.

The results showed that among the 31 healthy donors, the treatment of Skucilizumab resulted in two T cell lines from two different donors, and no specific T cell epitopes were found.
27 T cell lines from 15 different donors were obtained, 19 of which can determine specific T cell epitopes.

That is, compared with ecchizumab, the number of T cell epitopes induced by skuchizumab is smaller, and the in vitro immunogen is lower [14].

The above studies show that Recucci Yumab ​​is less immunogenic in vitro.

So, how is its immunogenicity in clinical trials? In the MEASURE series of meta-analysis, the incidence of ADAs in AS patients was only 0.
69% (Figure 10) [15] with Skuchiyu single treatment for 1 year; within 5 years of treatment, nearly 80% of patients had sustained symptoms and signs Relief and lasting effect [16].

The results of these large-scale clinical studies show that the immunogenicity of skukuzumab in clinical applications is low, which is consistent with the results of in vitro studies.

Figure 10: Results of immunogenicity analysis of 1164 patients in the 4 phase III studies of Skucilumab.
Figure 11: Within 5 years of treatment with Skucilumab, nearly 80% of patients experienced sustained relief of symptoms and signs and benefited from the effect Target, preparation process, degree of humanization and other multiple factors, among a variety of biological preparations used for AS treatment, Skucilizumab has the lowest immunogenicity, which is conducive to long-term escort for the treatment of AS during the marathon journey.

4 Summary All biological agents have immunogenic risks, and the ADAs they generate will have varying degrees of impact on the clinical efficacy and safety of drugs.

The immunogenicity of biological agents is affected by many different factors.
Among them, the targeting and degree of humanization of monoclonal antibodies are the key factors that affect the production of ADAs. Among the existing biological preparations used for the treatment of AS, the fully human IL-17A inhibitor Skuziyuumab is a biological preparation with lower immunogenicity, better efficacy and safety, which helps to optimize the clinical treatment outcome.
Help patients achieve the goal of good long-term prognosis.

Professor Wang Caihong’s continuous research and clinical application of biological agents have provided more options for the treatment of many rheumatic diseases, including AS, and quickly relieved the symptoms of AS patients.
However, after long-term treatment, the curative effect often weakened, hindering The key factor for the long-term efficacy and safety of biological agents is the immunogenicity of biological agents, that is, their ability to induce the production of ADAs.

ADAs can be produced through Td and Ti pathways.

Most of the persistent, non-neutralizing ADAs induced by biological agents are produced through the Td immune pathway, which can reduce the efficacy of biological agents.
The intensity of the response is affected by many factors such as the way of production and the degree of humanization.

Therefore, reducing the immunogenic response of biological agents is particularly important in the treatment of AS.

The arrival of IL-17A inhibitor-Skuchi Yumab ​​has become a boon for patients with AS.

Skukuzumab is a fully humanized monoclonal antibody.
Compared with other biological agents, the frequency of T cell response and the number of specific CD4+ T cells are significantly reduced, and the number of induced T cell epitopes is also reduced.
The immunogenicity is significantly reduced, the safety is higher, and the clinical problems and prognosis of patients with AS can be improved.

In 2020, we will move forward in exploration and fight the epidemic together.
With the arrival of 2021, the realization of the universalization of the new crown vaccine is also gradually advancing.

At the same time, the development of biologics has entered a new journey, and we look forward to opening a new chapter in the treatment of AS.

Dermatol Ther (Heidelb).
2018;8(1):57-68.
[13]Spindeldreher S, et al.
EADV.
2017: P1909.
[14]Spindeldreher S, et al.
MAbs.
2020,12(1): 1707418.
[15]Deodhar A, et al.
J Rheumatol.
2020;47(4):539-547.
[16]Baraliakos X et al.
RMD Open.
2019;5(2):e001005.
Looking back on "Treasure" Discovery Journey: IL-17A Quest, How does IL-17A, with "three heads and six arms", exert its diverse biological functions? Explore the key role of IL-17A in ankylosing spondylitis.
Why can it be a key target for treatment? Looking back at the story of monoclonal antibodies, and seeing how to continue the legend today