Currently, U.S. Food and Drug Administration (FDA) has approved 27 antibody drugs targeting CD20 in the world, and there are 93 biologics targeting CD20 in the clinical stage of development. Of these clinical projects, there are 22 CART-T gene therapies and 71 antibody drugs. Moreover, antibodies and gene therapy targeting CD20 have also made great progress in treating the disease.
On 29 March 2021, Therapeutics announced that it has completed the rolling submission of a Biologics License Application (BLA) to the FDA: a combination therapy (U2) of ublituximab (a novel glyco-engineered anti-CD20 monoclonal antibody) and Ukoniq (a PI3Kδ inhibitor) for the treatment of adult patients with chronic lymphocytic leukaemia (CLL). The FDA accepted the application on 29 May 2021. If approved, the U2 regimen will provide a new, chemotherapy-free option for patients with previously untreated (primary), and previously treated relapsed/refractory (treated) CLL/SLL. May 13, 2021 - Mustang Bio announced that interim data from an ongoing Phase 1/2 clinical trial of CD20-targeted autologous CAR-T cell therapy-MB-106 for high-risk B-cell Hodgkin's lymphoma (B-NHL) and chronic lymphocytic leukaemia (CLL) have been selected for inclusion in the 2021 European Haematology Society online conference with an e-poster presentation. Results show MB-106 for B-cell non-Hodgkin's lymphoma/leukaemia (CLL): up to 92% overall remission rate. So what is CD20? Why is it the focus of various pharmaceutical companies?
2. What is the Function of CD20?
3. What are the Ways of Treatment Targeting CD20?
CD20, also known as cluster of Differentiation 20, is a transmembrane protein encoded by the MS4A1 gene in human. The MS4A1 gene is 16 kb long located on chromosome 11q12.2, comprises eight exons, and several different CD20 mRNA transcripts have been annotated. The dominant CD20 mRNA variant is 2.8 kb long and uses all eight exons. The second most common form is 263 bases shorter, as it skips exon II. A minor 3.5 kb mRNA results from splicing exons in the upstream region into an internal 3' splice site located in exon I. However, all three transcripts are translated into identical full-length CD20 protein as the translation start codon is localized within exon III [1].
CD20 protein is a 33-37 kDa non-glycosylated protein expressed on the surface of normal and malignant B lymphocytes [2]. As the figure 1 shows, it consists of four hydrophobic transmembrane domains, one intracellular and two extracellular domains (large and small loops) with both N- and C- termini residing within the cytosol [3]. Currently, three CD20 isoforms (33, 35 and 37 kDa) resulting from different phosphorylation have been identified, and CD20 phosphorylation was reported to be higher in proliferating malignant B cells than in resting B cells [4].
Figure 1. The structure of CD20 molecule.
*This diagram is derived from reference 5.
CD20 is a cell surface tetraspan receptor expressed exclusively on B-lymphocytes, which are differentiated from pluripotent stem cells in the bone marrow and develop through the pro-B, pre-B, immature B and mature B stages. CD20 is present in the Pro-B to mature B cell stages, but is not expressed on haematopoietic stem cells, progenitor B cells or mature plasma cells. In addition to being expressed in normal B cells, CD20 is also expressed in tumor cells of B-cell origin, such as lymphomas and leukaemias. Despite it is, the function of CD20 has not been determined [6].
CD20 exists as an oligomer on the surface of B lymphocytes and available studies have demonstrated that CD20 forms tetramers on the surface of B cells. The interaction of CD20 with the membrane IgM (sIgM) of the B cell antigen receptor (BCR) has been demonstrated and upon activation of B cells, the BCR-CD20 complex dissociates and Phosphoproteins, calmodulin-binding proteins, are temporarily recruited to CD20 and are thus involved in intracellular signaling. Calcium flow has an important impact on the biological function of cells. Calcium pool-regulated calcium entry (SOCE), which increases intracellular calcium concentration through calcium-release-activated calcium (CRAC) channels, is the main way in which lymphocytes increase their intracellular calcium concentration. There is increasing evidence that CD20 is involved in SOCE and that CD20 has an important role in regulating intracellular calcium concentration [7] [8] [9].
As mentioned before, In addition to being expressed in normal B cells, CD20 is also expressed in tumor cells of B cell origin such as lymphoma and leukaemia, as well as in B cells involved in immune and inflammatory diseases. This makes CD20 become a target for the treatment of diseases such as lymphoma, leukaemia and certain autoimmune diseases. Currently, there are three main ways of treatment targeting CD20 in these disease, including anti-CD20 monoclonal antibodies, CAR-T and bispecific antibodies. In this section, we focus on anti-CD20 monoclonal antibodies.
Anti-CD20 monoclonal antibodies refer to monoclonal antibodies targeting CD20. Accumulating evidence suggests that anti-CD20 monoclonal antibodies kill tumors of B-cell origin and are associated with three mechanisms of action, namely antibody-dependent cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC) and direct effects caused by the binding of antibodies to CD20 molecules, including inhibition of cell growth, alteration of the cell cycle and apoptosis. ADCC refers that B cells coated with anti-CD20 are killed by a cell-based mechanism. CDC refers that the complement membrane attack complex is assembled on the cell surface (Figure 2).
Figure 2. Mechanism of action of anti-CD20 antibodies
*This diagram is derived from reference 10.
Since the approval of the world's first anti-CD20 monoclonal antibody (Roche's rituximab) in 1997, several anti-CD20 monoclonal antibodies have been approved worldwide. Depending on the degree of humanization and Fc fragment modification, anti-CD20 monoclonal antibodies can be divided into three generations. The first generation is represented by rituximab as a chimeric or mouse-derived monoclonal antibody, the second generation is represented by Arzerra from Genmab Inc. as a humanized monoclonal antibody and the third generation of anti-CD20 monoclonal antibodies is represented by Gazyva from Roche, whose Fc fragment of the antibody has been modified by glycosylation.
As mentioned before, there are 93 biologics targeting CD20 in the clinical stage of development. Here, we list projects in the clinical stage II and III.
Drug Name | Phase | Company | Diseases | Drug Type |
---|---|---|---|---|
H02 | Phase III | Lunan Pharmaceutical Group | Diffuse large B-cell lymphoma | Chimeric monoclonal antibodies |
Glofitamab | Phase III | Roche | Diffuse large B-cell lymphoma | Bispecific antibodies |
Mosunetuzumab | Phase III | Genentech Inc | Follicular centre lymphoma | Humanized monoclonal antibodies |
Rituximab biosimilar | Phase III | Hisun Pharma/Beijing Mabworks Biotech | Diffuse large B-cell lymphoma | Chimeric monoclonal antibodies |
Rituximab biosimilar | Phase III | Genor Biopharma |
Non-Hodgkin's lymphoma Diffuse large B-cell lymphoma |
Chimeric monoclonal antibodies |
Ocrelizumab biosimilar | Phase III | Cinnagen | Multiple Sclerosis | Humanized monoclonal antibodies |
Rituximab biosimilar | Phase III | CTTQ Pharma |
Non-Hodgkin's lymphoma Diffuse large B-cell lymphoma |
Chimeric monoclonal antibodies |
Recombinant chimeric anti-CD20 antibody | Phase III | Shanghai Institute of Biological Products | Diffuse large B-cell lymphoma | Chimeric monoclonal antibodies |
Recombinant humanized monoclonal antibody MIL62 | Phase III | InnoCare Pharma Limited |
Marginal zone B-cell lymphoma Follicular centre lymphoma |
Humanized monoclonal antibodies |
Rituximab biosimilar | Phase III | Boehringer Ingelheim |
Rheumatoid arthritis Follicular centre lymphoma |
Chimeric monoclonal antibodies |
Rituximab biosimilar | Phase III | Hualan Biological Engineering | Diffuse large B-cell lymphoma | Chimeric monoclonal antibodies |
Rituximab biosimilar | Phase III | Samsung Biologics; |
Rheumatoid arthritis Follicular centre lymphoma |
Chimeric monoclonal antibodies |
Ublituximab | Phase III | Tg Therapeutics; |
Multiple sclerosis Relapsing-remitting multiple sclerosis Marginal zone B-cell lymphoma Follicular centre lymphoma Chronic lymphocytic leukaemia Diffuse large B-cell lymphoma Set-cell lymphoma |
Chimeric monoclonal antibodies |
MB-106 | Phase II | Fred Hutchinson Cancer Research Center | Non-Hodgkin's lymphoma | CAR-T |
Anti-CD20 CAR T-cell therapy | Phase II | Shanghai Longyao Biotechnology | Diffuse large B-cell lymphoma | CAR-T |
Anti-CD19 and anti-CD20 CAR-T cell therapy | Phase II | The Medical College Of Wisconsin Nonprofit; | Tumor | CAR-T |
CPO-107 | Phase II | Conjupro Biotherapeutics Inc; | Diffuse large B-cell lymphoma | Fusion protein |
MRG001 | Phase II | miracogen | COVID19 | ADC |
4SCAR-T cell therapy | Phase II | Shenzhen Geno-Immune Medical Institute | Tumor | Biologics |
Anti-CLEVER-1 antibodies | Phase II | Faron Pharmaceuticals | Tumor | Fully human monoclonal antibody |
Allogeneic anti-CD20 CAR-T cell therapy | Phase II | Precision Biosciences |
Non-Hodgkin's lymphoma Chronic lymphocytic leukaemia |
CAR-T |
MB-CART2019.1 | Phase II | Miltenyi Biotec |
Chronic lymphocytic leukaemia Diffuse large B-cell lymphoma Non-Hodgkin's lymphoma |
CAR-T |
BCD-132 | Phase II | Biocad | Multiple sclerosis | Humanized monoclonal antibodies |
DI-Leu16-IL2 | Phase II | Merck Serono | Non-Hodgkin's lymphoma | Fusion protein |
Dual specificity CD19 and CD20 or CD22 CAR-T cell | Phase II | Chinese PLA General Hospital |
B-cell lymphoma Leukaemia |
CAR-T |
MB-CART20.1 | Phase II | Miltenyi Biotec; | Non-Hodgkin's lymphoma | CAR-T |
BVX20-CD20 antibody | Phase II | Biocon;Vaccinex; | Non-Hodgkin's lymphoma | Humanized monoclonal antibodies |
MT-3724 | Phase II | Molecular Partners Ag; |
B-cell lymphoma Chronic lymphocytic leukaemia Diffuse large B-cell lymphoma Haematological neoplasm |
Single chain Fv fragment antibody |
Odronextamab | Phase II | Regeneron Pharmaceuticals Inc; |
Follicular centre lymphoma Non-Hodgkin's lymphoma |
Bispecific antibodies |
Anti-CD20 CART-transduced T cells (Cellular Biomedicine Group) | Phase II | Chinese PLA General Hospital |
B-cell lymphoma Leukaemia |
CAR-T |
Veltuzumab | Phase II | Immunomedics Inc; |
Non-Hodgkin's lymphoma Idiopathic thrombocytopenic purpura |
Humanized monoclonal antibodies |
Anti-CD3 anti-CD20 bispecific antibody | Phase II | Genmab; | Blood Tumours | Humanized monoclonal antibodies |
Recombinant Human B-lymphocyte antigen CD20(MS4A1)-VLPs (Active) (CSB-MP015007HU)
References
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[2] Tedder TF, Klejman G, Schlossman SF, et al. Structure of the gene encoding the human B lymphocyte differentiation antigen CD20 (B1) [J]. J Immunol. 1989; 142 (7):2560-2568.
[3] Eon Kuek L, Leffler M, Mackay GA, Hulett MD. The MS4A family: counting past 1, 2 and 3 [J]. Immunol Cell Biol. 2016; 94(1): 11-23.
[4] Tedder TF, Schlossman SF. Phosphorylation of the B1 (CD20) molecule by normal and malignant human B lymphocytes. J Biol Chem. 1988, 263(20): 10009-10015.
[5] Shundong Cang, Nikhil Mukhi, Kemeng Wang, et al. Novel CD20 monoclonal antibodies for lymphoma therapy [J]. Journal of Hematology & Oncology. 2012, 5:64.
[6] Riley JK, Sliwkowski MX. CD20: a gene in search of a function [J]. Semin Oncol. 2000 Dec. 27 (6 Suppl 12): 17-24.
[7] ]Polyak M J, Li H, Shariat N, et al. CD20 homo-oligomera physieally associate with the B cell antigen receptor [J]. BiolChem. 2008, 283 (27): 18545-18552.
[8] Polyak M J, Deans J P. Alanine-170 and proline-172 are critical determinants for extracellular CD20 epitopes; beterogeneity in the fine specificity of CD20 monoclonal antibodies is defined by additional requirements imposed by both amino acid sequence and quaternary structure [J]. Blood. 2002. 99(9): 3256-3262.
[9] Pierce S K. Lipid rafts and B-cell activation [J]. NatlRevImmunol. 2002, 2 (2): 96-105.
[10] Browning, J. B cells move to centre stage: novel opportunities for autoimmune disease treatment [J]. Nat Rev Drug Discov. 2006, 5, 564–576.
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