The U.S. FDA has approved more than 100 antibody drugs in 35 years

It has been 35 years since the US FDA approved the first monoclonal antibody drug in 1986.

Antibody drugs: from zero to the outbreak stage

In 1986, the world's first murine monoclonal antibody drug OKT3 (muromonab-CD3) was approved by the FDA, creating a precedent for the use of monoclonal antibodies for disease treatment.

The article pointed out that this development law and trend is a timetable worthy of reference for drug developers who promote antisense oligonucleotide therapy, mRNA therapy and targeted protein degradation agents.

▲Data distribution of the top 100 antibody drugs approved by the FDA (picture source: reference [1])

Monoclonal antibodies have attracted much attention from drug developers because of their excellent specificity and affinity for cell surface target antigens.

The more attractive advantage is that in the past, medicinal chemists may have spent years searching for small molecules that are active on specific targets, but the discovery of antibodies may only take a few months.

The article pointed out that although the number of approved antibody drugs has reached 100, the targets they cover are still very limited.

▲Top targets of the top 100 antibody drugs approved by the FDA (picture source: reference [1])

Especially in recent years, the huge potential of antibody drugs has been tapped, showing explosive growth.

Some other target immunosuppressants have also been successful, and multiple antibody drugs targeting TNF and IL-6 signaling pathways have been approved by the FDA.

Data show that there are still nearly 870 antibodies in clinical development, and about 36% of the pipeline is focused on 10 validated targets.

Remarks: a: The total number includes bispecific antibodies; b: 42 models target PD-1, and 38 models target PD-L1.

It is reported that in China, the antibody pipeline for PD-1/PD-L1, HER2, CTLA-4, EGFR and CD20 is the most abundant, and some of the newer targets include 4-1BB, LAG3 and CD47.

The article reviews pointed out that this trend is reasonable, because when people see a feasible method, they want to do better.

The data also shows that in the antibody field, cancer treatment research continues to dominate, followed by dermatology and blood disease pipelines.

Picture source: reference [1]

In addition, with the advent of COVID-19, there are more than 20 kinds of antibodies against the new coronavirus in the clinic, some of which have obtained emergency use authorization (EUA) from the FDA and have not yet been fully approved.

After "classic antibodies", diversified antibodies such as ADCs and double antibodies emerged

The article mentioned that most of the approved antibody products so far are called "classic" antibodies.

With the maturity of antibody discovery technologies and methods, antibody drug development is becoming more and more diverse, including antibody conjugated drugs (ADC), bi/multispecific antibodies, nanobodies and other forms of antibodies are increasing.

Among them, ADC has attracted much attention.
It is known as a "biological missile" because it can achieve precise strikes on cancer cells.
Pfizer's gemtuzumab ozogamicin targeting CD33 is the world's first ADC approved by the FDA.
It is composed of anti-CD33 monoclonal antibody and calicheamicin.
The former can bind to CD33 protein and play a role in localization; the latter is a highly toxic cytotoxin that plays a bullet role.
After the drug was first approved by the FDA in 2000, it experienced the twists and turns of delisting, and was approved again in September 2017 to treat CD33-positive acute myeloid leukemia (AML).

Within 10 years after the first ADC was first approved, no other drugs in the ADC drug development field have been approved.
It was not until 2011 that the FDA approved the second ADC, Seattle Genetics' CD30-targeting antibody conjugate drug brentuximab vedotin.
In the following 10 years, this field has achieved relatively rapid development.
As of now, this number has risen to 10, including the 101st antibody approved by the FDA not long ago-ADC Therapeutics, a CD19-targeting antibody-conjugated drug loncastuximab tesirine, to treat relapsed/refractory large B-cell lymphoma Adult patients.
This is also the first FDA-approved antibody conjugate drug targeting CD19.

The “Nature” sub-issue article pointed out that for the development of next-generation ADCs, conjugation strategies and finding new payloads have always been the direction of drug research and development personnel.
Some companies are also expanding ADC research and development beyond cancer treatment.
For example, ABBV-3373 developed by AbbVie is an ADC formed by coupling an antibody targeting TNF with a glucocorticoid receptor modulator, which is being developed for the treatment of rheumatoid arthritis.

Bispecific antibodies have also become a rising star in this field.
The FDA has approved two bispecific drugs, and nearly 160 bispecific and multispecific drugs are in clinical trials.
Different from the single targeting of monoclonal antibodies, bispecific antibodies contain two specific antigen binding sites, which can bind to different epitopes, such as stimulating a targeted immune response or enhancing the killing function of tumor cells.

In 2014, the FDA approved Amgen's blinatumomab, a bispecific antibody targeting CD19 and CD3, to treat relapsed or refractory B-cell acute lymphoblastic leukemia.
It can bind to CD19 at one end to capture malignant B lymphocytes, and bind to CD3 at the other end to recruit T cells, and mediate the lysis of cancer cells by T cells by connecting the two.
The dual-antibody drug was approved for marketing in China in December 2020.
In the field of anti-cancer research, related research on the use of bispecific antibodies for the treatment of solid tumors is underway.

With the FDA's approval of Roche's emicizumab to treat hemophilia A in 2017, it proved that bispecific antibodies can not only promote T cell recruitment, but also play more other roles.
Iimerizumab promotes the production of thrombin by bridging the coagulation factors FIXa and FX to restore the coagulation function of patients with hemophilia A.
In China, it has been approved for simultaneous use in the preventive treatment of hemophilia A patients with or without factor VIII inhibitors.

Researchers are further exploring bispecific antibody strategies, hoping to introduce them into the brain and other inaccessible organs.
For example, Roche uses its unique brain shuttle technology to combine anti-amyloid monoclonal antibody gantenerumab with transferrin receptor (TfR1) antibody fragments, allowing it to more effectively cross the blood-brain barrier, thereby increasing its effectiveness.
The effect of degrading Aβ in the brain.
Currently, Roche's therapy is in clinical development.

Some institutions and researchers also have high hopes for Nanobodies.
Nanobodies are antibodies that only contain naturally occurring heavy chains and are much smaller in size than ordinary antibodies.
Their unique structure makes them ideal materials for new biological drugs.
In 2019, the world's first nanobody caplacizumab developed by Sanofi's Ablynx company was approved by the FDA for the treatment of acquired thrombotic thrombocytopenic purpura.
Ablynx is developing more than 40 nanobody drug candidates for use in cancer, autoimmune diseases, respiratory diseases, blood diseases and other fields.
At the same time, more nanobody pipelines in the global field are also increasing.
In China, caplacizumab will enter the third batch of clinically urgently needed overseas new drugs in 2020.
Some Chinese companies have also begun to explore the field of nanoantibodies, and related pipelines have entered the late clinical stage.

In addition, the article also pointed out that although many therapeutic antibodies can block the interaction between receptors and ligands, agonist antibodies that mimic natural ligands to activate cell signaling are still out of reach.
In the field of agonists, for example, GlaxoSmithKline’s ICOS agonist antibody is undergoing phase 3 clinical trials; 4-1BB research is also considered to be expected to be developed into agonist drugs.
In addition, drug developers are also getting involved in antibody-protein fusion biological products, and some antibodies fused with cytokines, receptor ligands, peptides, etc.
are also expected to open up new possibilities for drug development.

With the advancement of more antibody technologies, it is believed that more good drugs and new drugs will be born in the broader field of antibodies in the future, bringing treatment options and improving lives for patients.
As the article points out, the approval of 100 antibody drugs may be just the beginning, and the next "100" will be even faster.

Reference materials:

[1]FDA approves 100th monoclonal antibody product.
Retreived May 05 2021.
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