Continuing from the previous issue, nanobodies have been used in the treatment and diagnosis of various malignant diseases
due to their low immunogenicity, high specificity, and high stability. In today's blog, we will introduce four more popular targets
of antibody drugs.
Table 1. Basic information of popular targets introduced in this issue
The CTLA-4 (cytotoxic T lymphocyte antigen 4) gene was first discovered by French scientists in 19871, and its function was
subsequently revealed (Figure 1). CTLA-4, a member of the immunoglobulin superfamily, is a checkpoint molecule that mainly
performs signal transduction and immune regulation between immune cells (such as T cells) and antigen-presenting cells.
CTLA-4 and CD28 can bind to the same ligands (CD80 and CD86), but their functions are opposite. CTLA-4 is a key inhibitory
receptor, playing an important role especially in the initiation phase of the immune response.
In resting T cells, CTLA-4 is located inside the cell, but it will be transported to the surface of T cells when T cells are activated
by CD28 stimulation. CTLA-4 competes with CD28 for binding and blocks T cell activation, thereby inhibiting T cell activation
Through this function, CTLA-4 can inhibit the immune system from attacking the body's own tissues, avoiding the occurrence
of autoimmune diseases, and may also prevent T cells from attacking tumor cells. Therefore, drugs targeting CTLA-4 have been
widely used in the field of tumor treatment.
Figure 1. The function mechanism of CTLA-4
CTLA-4 monoclonal antibody (Ipilimumab, Bristol-Myers Squibb, approved for the treatment of advanced melanoma in the
United States in 2011) is an early-developed immune checkpoint inhibitor that appeared before PD-1 monoclonal antibody.
But it was surpassed by PD-1 monoclonal antibody and was no longer recommended as a single drug for first-line treatment
of advanced melanoma later on due to its high toxicity and limited curative effectiveness.
The clinical research progress of Tremelimumab, another CTLA-4 monoclonal antibody drug, is relatively tortuous. It was approved
by the FDA as an orphan drug for the treatment of malignant mesothelioma (MM) in 2015. In 2017, 2019 and 2020, its
phase III clinical trials for non-small cell lung cancer (NSCLC) or bladder cancer all failed.
In February 2020, it was again granted orphan drug qualification for the treatment of hepatocellular carcinoma (Hepatocellular
carcinoma HCC) by the FDA. As hIgG2 subtype, Tremelimumab has no ADCC effect and its single-drug efficacy is relatively poor.
In order to solve the dilemma faced by CTLA-4 monoclonal antibody drugs, bispecific antibodies and nanobodies have become
the game-breakers. For example, the tetravalent antibody Cadonilimab targeting PD-1/CTLA-4, KN046 targeting the PD-L1/CTLA-4,
and AstraZeneca' s bispecific antibody MEDI5752 targeting PD-1/CTLA-4, they all have strong anti-tumor activities. In addition,
a nanobody drug developed by Harbor BioMed called HBM4003, has been engineered to significantly enhance ADCC and increase
Treg cell exhaustion.
Figure 2. Mechanism of action of immunotherapies targeting BCMA3
BCMA (B cell maturation antigen) is a member of the tumor necrosis factor (TNF) receptor family and a transmembrane protein
expressed on mature B cells and plasma cells. BCMA is mainly involved in physiological processes such as immune system
regulation and inflammatory response by mediating the signal transduction pathway in the process of B cell to plasma cell
In the field of oncology, BCMA has also become one of the therapeutic targets for multiple myeloma (MM). Currently, monoclonal
antibody drugs, targeted drugs, and CAR-T cells targeting BCMA all have been widely explored (Figure 2)3.
Among them, BCMA monoclonal antibody drugs rely on antigen specificity, can directly act on the surface of multiple myeloma
(MM) cells by recognizing BCMA, and promote anti-tumor activity mediated by macrophages; while CAR-T cells have the
specificity to target and kill CD19- and CD38+ malignant plasma cells, which makes CAR-T cell therapy targeting BCMA may
have a significant therapeutic effect on some difficult-to-cure cancers such as MM.
In 2022, the first nanobody CAR-T cell targeting BCMA developed by Legend Biotech was approved by the FDA for marketing.
It was China's first cell product to enter the US market.
VEGF (vascular endothelial growth factor) is a vascular endothelial cell growth factor, which is overexpressed in many tumors.
VEGF can promote the formation of new blood vessels and provide nutrients and oxygen to tumors, thereby promoting tumor
growth and metastasis (Figure 3). As a result, VEGF has become an important target.
Figure 3. The combination of VEGF and its receptor can promote angiogenesis
A variety of antibody drugs against VEGF have been developed, including:
Bevacizumab: It was approved by the US FDA in 2004 and has been approved for the treatment of various cancers, including
advanced colorectal cancer, lung cancer, breast cancer, kidney cancer, and malignant glioma.
In China, the drug was approved in 2010 for the treatment of metastatic colorectal cancer, and in 2015 as a first-line treatment
for advanced, metastatic or recurrent non-squamous non-small cell lung cancer; aflibercept (aflibercept) is an Fc fusion protein
that binds VEGF developed by Regeneron.
It was approved by the US FDA in 2011. Currently, aflibercept is approved in Europe and the United States for the treatment
of four diseases, namely wet age-related macular degeneration (AMD), macular edema secondary to central retinal vein occlusion
(CRVO-ME), diabetic macular edema (DME) and Visual impairment due to myopic choroidal neovascularization (mCNV).
In China, Aflibercept was approved by the State Drug Administration on February 13, 2018, for the treatment of diabetic macular
edema (DME); Conbercept was developed by Chengdu Kanghong Biotechnology Co., Ltd. The new generation of anti-VEGF
fusion protein is also the first biological new drug with fully independent intellectual property rights that has obtained the
international general name of the WHO.
Conbercept was approved for marketing in 2013, and its initial indication was age-related macular degeneration (AMD).
In 2017, it gained a new indication - vision loss due to choroidal neovascularization (pmCNV) secondary to pathological myopia (PM).
New indications such as RVO-ME and DME have entered phase III clinical trials in December 2020. These drugs can
inhibit the activity of VEGF through different mechanisms, thereby preventing the formation of tumor blood vessels and
achieving the effect of treating diseases.
Tumor Necrosis Factor (TNF) is a type of cytokine mainly produced by macrophages. It has multiple biological functions,
including regulating the activation, proliferation, and differentiation of immune cells, promoting inflammatory responses,
and inducing apoptosis (Figure 4) 4. TNF-α (Tumor Necrosis Factor-α) is the most common and functionally important member
of the TNF family.
Figure 4. TNF-α signaling pathway 4
Since TNF-α plays a key role in many inflammatory and autoimmune diseases, inhibiting the biological activity of TNF-α can be
an effective strategy for thetreatment of such diseases. Anti-TNF-α drugs mainly refer to monoclonal antibodies or soluble receptor
proteins against TNF-α, which can inhibit its biological activity by interfering with the binding of TNF-α to its receptor. At present,
a variety of anti-TNF-α drugs have been used in clinical treatment:
Infliximab: It is a mouse-human chimeric monoclonal antibody, mainly used for the treatment of rheumatoid arthritis, ankylosing
spondylitis, Crohn's disease (Crohn's disease, CD) and ulcerative colitis, etc. Inflammatory disease.
Adalimumab: It is a fully humanized monoclonal antibody suitable for a variety of autoimmune diseases, such as rheumatoid arthritis,
ankylosing spondylitis, psoriatic arthritis, Crohn's disease and Ulcerative colitis, etc.
Golimumab: It is a fully humanized monoclonal antibody that can be used to treat diseases such as rheumatoid arthritis,
ankylosing spondylitis, psoriatic arthritis and ulcerative colitis.
Ozoralizumab (also known as ATN-103) is a skeleton-optimized fully human nanobody drug targeting tumor necrosis factor-α (TNF-α).
It inhibits its biological activityby specifically binding and neutralizing TNF-α, so as to achieve the purpose of treating
inflammation-related diseases. The main research and development intention of Osolazumab is to improve the safety and tolerability
of existing anti-TNF-α drugs.
Due to its unique "trimeric" structure, osolazumab has lower molecular weight and higher selectivity, and can accumulate in the joint
cavity and maintain long-term biological activity.
This makes osolazumab potentially reduce the risk of infection and other systemic side effects while maintaining efficacy compared
with traditional anti-TNF-α drugs.At present, osolazumab is mainly studied in the treatment of autoimmune diseases, such as
rheumatoid arthritis and ankylosing spondylitis. Clinical trials have shown that osolazumab has shown good safety and tolerability
in the treatment of diseases such as rheumatoid arthritis.
V565 is an oral TNFα nanobody drug, which has completed phase II clinical trials. Antibody to TNFα is very effective in the treatment
of Crohn's disease, but the main method of administration is intravenous injection or subcutaneous injection, while V565 innovatively
adopts oral administration method.
The Phase II clinical trial of V565 uated the efficacy of oral V565 in patients with active CD for 6 weeks. The study included
125 patients with ileum or colon disease, randomly assigned 2/3 of them to receive oral V565 treatment, 1/3 received placebo treatment,
and the follow-up time was 28 days.
The primary outcome measure was clinical response, defined as a reduction in CDAI-70 (Crohn's disease activity index) at day 42,
and a reduction in inflammatory markers. The results of the study showed that there was no significant difference in the clinical
remission rate between the two groups (35.4% in the V565 group, 37.2% in the placebo group), but the endoscopic improvement
rate was higher in the treatment group (56.3% in the V565 group, 30.0%). The incidence of serious adverse events was similar
between the two groups.
1. Brunet, J.-F. et al. A new member of the immunoglobulin superfamily—CTLA-4. Nature 328, 267-270 (1987).
2. Van Coillie, S., Wiernicki, B. & Xu, J. Molecular and cellular functions of CTLA-4. Regulation of Cancer Immune Checkpoints: Molecular and Cellular Mechanisms and Therapy, 7-32 (2020).
3. Cho, S.-F., Anderson, K. C. & Tai, Y.-T. Targeting B cell maturation antigen (BCMA) in multiple myeloma: potential uses of BCMA-based immunotherapy. Frontiers in immunology 9, 1821 (2018).
4. Leone, G. M., Mangano, K., Petralia, M. C., Nicoletti, F. & Fagone, P. Past, Present and (Foreseeable) Future of Biological Anti-TNF Alpha Therapy. Journal of Clinical Medicine 12, 1630 (2023).