Industry Trends

Wondering which Antibody Targets to Learn in 2023?(Part 1/2)

15-08-2023
FOREWORD

In recent years, antibody therapy (including traditional antibodies and nanobodies) has become an important means of treating a variety
of human malignant diseases. So far there's more than 100 antibody therapies have been approved for clinical use.

Since 2014, the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have approved 6-13 antibody
therapeutics each year, and this market share is growing rapidly. The main form of antibody approved for marketing is IgG, and there are
also bispecific antibodies, trivalent antibodies, and antibody fragments.

Currently, antibody therapeutics are most commonly used in the clinic to treat diseases such as cancer, autoimmune diseases and chronic
inflammation. With the continuous emergence of new antibodies such as nanobody therapy, antibody therapy has also been widely explored
and applied in the treatment of infectious diseases, blood diseases, nervous system diseases, ophthalmological diseases, metabolic diseases,
musculoskeletal diseases and organ transplantation.

 

We will share with you the 8 popular targets of antibody therapy in two blogs and here's the first patch:
 

Her2, EGFR, CD19, CD20, CTLA-4, BCMA, VEGF, and TNFα.

 


Table 1. Basic information of popular targets introduced in this blog.


 
  • HER2


HER2 (uniprot: P04626) is the abbreviation of Human Epidermal growth factor Receptor 2. It is a member of the receptor tyrosine kinase
family in the human body. Under normal circumstances, HER2 is mainly involved in the regulation of cell growth and differentiation.

It is usually expressed on the cell membranes of epithelial cells in various organs (such as breast and skin), as well as in the gastrointestinal
tract, respiratory tract, reproductive system and urinary tract. It can also be led to abnormal cell proliferation and tumor formation when
mutated or overexpressed.

 

The HER2 protein, also known as ErbB2, is located on the 17q12 region of the human chromosome. HER2 overexpression occurs in about
15-30% of breast cancer and 10-30% of gastric/gastroesophageal cancer. It is a marker associated with breast cancer,
gastric/gastroesophageal cancer and other malignant tumors.

HER2 Expression is also found in other cancers, such as ovarian cancer, endometrial cancer, bladder cancer, lung cancer, colon cancer,
and head and neck cancer, so the detection of HER2 is of great significance in the diagnosis, treatment and prognosis of these tumors.

HER2-positive means that HER2 protein on the surface of tumor cells is overexpressed or gene amplification occured, suggesting that
this type of cancer cell may be sensitive to HER2-targeted therapy. There are three main mechanisms of action of anti-HER2 therapeutic
antibodies (Figure 1) :

 

  • 1. By blocking HER2 from receiving growth signals from HER2-positive breast cancers, anti-HER2 drugs can slow down or prevent

             HER2-positive breast cancer from growing by blocking growth signals
 

  • 2. Initiate ADCC (antibody-dependent cell-mediated cytotoxicity) effect, mediate killer cells to directly kill target cells;
 
  • 3. Couple with small molecule drugs to achieve the purpose of killing target cells . HER2 antibodies can also be used in the immune
             molecular imaging of HER2, such as the nano-antibody imaging agent 68GaNOTA-Anti-HER2 VHH1 (NCT03331601), which has
             already entered the clinical phase 2.



Figure 1. Mechanism of action of current anti-HER2 therapies. Monoclonal antibodies (trastuzumab and pertuzumab),
Fc-optimized antibodies (margetuximab), tyrosine kinase inhibitors (lapatinib, neratinib, and tucatinib), and
antibody-drug conjugates (ado-trastuzumabemtansine and trastuzumab-deruxtecan)1



 

  • EGFR


EGFR (epidermal growth factor receptor) is a transmembrane tyrosine kinase receptor, which belongs to the ErbB receptor family just like HER2.
EGFR is normally expressed in a low amount in skin, liver and other tissue cells. EGFR abnormalities or mutations have been linked to a variety
of diseases, such as non-small cell lung cancer (NSCLC), colorectal cancer, breast cancer, head and neck cancer, and other cancers, as well as
kidney disease and certain skin diseases (such as psoriasis and atopic dermatitis).

The high expression of EGFR can promote the proliferation, survival and invasion of cancer cells, thus leading to the occurrence and development
of tumors.

At present, a variety of therapeutic drugs against EGFR have been developed, including monoclonal antibodies (such as cetuximab, nimotuzumab,
panitumumab, etc.), which mainly inhibit the activity of EGFR by blocking the combination of growth factors and EGFR, so as to achieve the effect
of treating tumors (Fig. 2)2.



Figure 2. The mechanism of Etuximab, Nimotuzumab and Panitumumab inhibiting EGFR and the two main
signaling pathways downstream of EGFR (RAS-RAF-MAPK and PI3K-PTEN-AKT)2



 

  • CD19


CD19 is a single transmembrane glycoprotein3 widely expressed on the surface of B cells. It plays an important role in B cell development,
differentiation and functional regulation. CD19 is expressed on the surface of leukemia cells in more than 90% of acute lymphoblastic leukemia (ALL)
patients. Therefore, CD-19 has become an important target in the treatment of hematological malignancies, especially for the treatment of
B lymphoma and acute lymphoblastic leukemia (ALL).

Therapeutic drugs targeting CD19 mainly include CAR-T cell therapy (such as CD19/20 bispecific nanobody-derived CAR-T cell therapy, NCT03881761)
and bispecific antibodies (such as blinatumomab), etc. These drugs can induce apoptosis of B cells or activate T cells to attack tumor cells through
different mechanisms (Figure 3)4.



Figure 3. Targeting CD19 antibody design strategy and mechanism of action4


 

  • CD20


CD20 is a B cell-specific membrane glycoprotein that is widely expressed on the surface of B lymphocyte precursors, mature cells, and memory
B cells, and participates in biological processes such as B cell differentiation, proliferation, and antibody production.

CD-20 has become one of the targets for the treatment of these diseasesis due to its high expression on B cells of patients with B lymphoma
and some autoimmune diseases.

At present, a variety of CD-20 antibody products have been developed, such as the above-mentioned nanobody CAR-T therapy (NCT03881761),
Rituximab, Ofatumumab and Ublituximab for the treatment of non-Hodgkin's lymphoma or chronic lymphocytic leukemia, and chimeric proteins
(such as Obinutuzumab), idiopathic lesion-dissolving drugs (TOTEM) for the treatment of rheumatoid arthritis, and Ocrelizumab for adult
relapsing multiple sclerosis (MS). These therapies or drugs can induce apoptosis of B cells through different mechanisms (Figure 4)5, so as to
achieve the therapeutic effect.



Figure 4. The structure, binding epitope and mechanism of action of some antibodies targeting CD20;
CDC, complement dependent cytotoxicity;ADCC, antibody-dependent cellular cytotoxicity; RTX,
rituximab; OCR, ocrelizumab; OFA, ofatumumab; UTX, ublituximab5.



CONCLUSION

Antibody drugs or therapies, nanobodies included, have a wide range of application fields and have extremely high applications. The development
of specific antibody drugs for different targets will become one of the most important development directions in the field of biomedicine in the
future. The above are just some of the more popular antibody targets at present.

With the progress of scientific research and the development of technology, new antibody targets are constantly emerging. In specific research
and treatment, selecting an appropriate target needs to comprehensively consider factors such as tumor type, patient characteristics, and
drug safety and effectiveness.

In our next blog, we will continue to introduce the other four popular targets ---- BCMA, CTLA-4, VEGF, and TNFα.



1. Wynn, C. S. & Tang, S.-C. Anti-HER2 therapy in metastatic breast cancer: many choices and future directions. 
Cancer and Metastasis Reviews 41, 193-209, doi:10.1007/s10555-022-10021-x (2022).

2. Han, C.-B., Ma, J., Li, F. & Zou, H.-w. Molecular Markers for the Prediction of Anti-EGFR Monoclonal
Antibody Treatment Efficacy in Metastatic Colorectal Cancer. Journal of Cancer Therapy 02, 675-682 (2011).

3. Wang, K., Wei, G. & Liu, D. CD19: a biomarker for B cell development, lymphoma diagnosis and therapy. 
Experimental Hematology & Oncology 1, 36, doi:10.1186/2162-3619-1-36 (2012).

4. Kellner, C., Peipp, M., Gramatzki, M., Schrappe, M. & Schewe, D. M. Perspectives of Fc engineered antibodies
in CD19 targeting immunotherapies in pediatric B-cell precursor acute lymphoblastic leukemia. 
Oncoimmunology 7, e1448331 (2018).

5. de Sèze, J. et al. Anti-CD20 therapies in multiple sclerosis: From pathology to the clinic. 
Frontiers in Immunology 14, doi:10.3389/fimmu.2023.1004795 (2023).

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