Overview of CD20-Targeted CAR Cell Therapies

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Backgrounds of CD20

CD20, also known as B-lymphocyte surface antigen B1, transmembrane 4 structural domain subfamily A member 1 and MS4A1, is a B-lymphocyte surface-specific membrane protein in a non-glycosylated form. CD20 is composed of 297 amino acids and has a relative molecular weight of 33-35 kDa. It consists of four transmembrane domains, one intracellular ring, and two extracellular ring domains, with both the N-terminus and C-terminus located in the cytoplasm. The human CD20 gene is a single copy gene, located on chromosome 11q12.13.1, 16 kp long, with eight exons. Exon I contains the transcription start site, exon III contains the translation start site, exon V is sheared off during splicing, and exon VI encodes the untranslated region at the 3' end of the mRNA of the CD20 molecule. mRNA of the CD20 molecule exists in three forms: the first mRNA is 2.8 Kb long and contains the complete sequence from exon I to exon V. This mRNA is the main form. The second mRNA is 263bp shorter than the former due to the splicing of exon I and exon III, and the third mRNA is 3.4kb long, which is generated by a sequence upstream of exon I that is involved in the splicing within exon I. This form of mRNA is less common.

Fig.1 Structure of CD20

CD20 Signaling Pathways

CD20 is highly expressed on the surface of normal B cells and most malignant B cells. Many studies have shown that it functions as a regulator of calcium channels. Upon binding of the B cell receptor (BCR) to the antigen, CD20 detaches from the BCR complex and forms homo tetramers, which regulate certain calcium ions necessary for antibody response. CD20 is expressed in both early B lymphocytes and mature B lymphocytes, but its expression ceases when they differentiate into plasma cells. CD20 plays an important role in the immune system by triggering intracellular tyrosine kinase signaling, regulating intracellular calcium levels, inducing the accumulation of c-Myc mRNA, and regulating B cell growth and differentiation. The development of immunity requires functional BCR signaling pathways and CD20 has been reported to co-localize in lipid rafts and physically interact directly with the BCR. In addition, it has been observed that mitogen-stimulated CD20 becomes highly phosphorylated and that CD20 functions as a calcium channel and participates in B-cell activation. It has also been shown that cell surface CD20 levels on primary chronic lymphocytic leukemia (CLL) cells correlate with (and may co-regulate) cell surface BCR expression. These studies suggest that CD20 is physiologically directly required for effective BCR signaling in B cells.

CD20 has been expressed in more than 95% of B lymphocytic tumors, and its ease of binding to antibodies that do not readily detach after binding makes the CD20 molecule an ideal target antigen for the treatment of B-cell lymphoma. Moreover, targeting CD20 can also help disrupt the BCR signaling pathway and slow or stop the growth of cancer cells. Chimeric antigen receptor T cell (CAR) therapy can be used to genetically modify a patient's T cells to express a receptor that recognizes and binds to CD20. These modified T cells are then injected into the patient, where they can specifically and accurately recognize CD20 and kill CD20-expressing cancer cells, thereby stopping the growth of cancer cells.

Clinic Status of CD20-Targeted CAR Cell Therapies

Clinical trials of CAR-T cell therapy targeting CD20 have shown promising results with an overall efficiency of 79% in patients with relapsed or refractory NHL treated with CD19 and CD20 dual-targeted CAR-T therapy. To date, ongoing clinical trials of CD20-targeted CAR therapy have focused on non-Hodgkin's lymphoma (NHL), multiple myeloma (MM), acute lymphoblastic leukemia (ALL), and melanoma. Areas of focus for these trials include CD20/CD19 combination therapies and next-generation CAR design and maintenance therapies. The majority of these ongoing clinical trials are in Phase I, with only a few entering Phase II status. A few of these CD20-targeted CAR cell therapy trials are also being used experimentally in various other immune-related diseases such as immune thrombocytopenic purpura (ITP), systemic lupus erythematosus (SLE), myasthenia gravis (MG), and rheumatoid arthritis (RA).

Table 1. Ongoing CD20-Targeted CAR Cell Therapy Clinical Trials

NCT Number

Title

Status

Conditions

Sponsor/Collaborators

Phases

NCT04007029	Modified Immune Cells (CD19/CD20 CAR-T Cells) in Treating Patients With Recurrent or Refractory B-Cell Lymphoma or Chronic Lymphocytic Leukemia	Recruiting	CD19 Positive\|CD20 Positive\|Recurrent Chronic Lymphocytic Leukemia\|Recurrent Diffuse Large B-Cell Lymphoma\|Recurrent Follicular Lymphoma\|Recurrent Mantle Cell Lymphoma\|Recurrent Primary Mediastinal (Thymic) Large B-Cell Cell Lymphoma\|Recurrent Small Lymphocytic Lymphoma\|Refractory Chronic Lymphocytic Leukemia\|Refractory Diffuse Large B-Cell Lymphoma\|Refractory Follicular Lymphoma\|Refractory Mantle Cell Lymphoma\|Refractory Primary Mediastinal (Thymic) Large B-Cell Cell Lymphoma\|Refractory Small Lymphocytic Lymphoma	Jonsson Comprehensive Cancer Center\|Parker Institute for Cancer Immunotherapy	Phase 1
NCT04697940	Decitabine-primed Tandem CD19/CD20 CAR-T Cells Treatment in r/r B-NHL	Recruiting	Relapsed and Refractory B-cell Non-Hodgkin's Lymphoma\|Decitabine-primed Tandem CD19/CD20 CAR-T Cells	Han weidong\|Chinese PLA General Hospital	Phase 1\|Phase 2
NCT04735471	A Safety and Efficacy Study of ADI-001, an Anti-CD20 Allogeneic Gamma Delta CAR-T, in Subjects With B Cell Malignancies	Recruiting	Lymphoma, Follicular\|Lymphoma, Mantle-Cell\|Marginal Zone Lymphoma\|Primary Mediastinal B-cell Lymphoma\|Diffuse Large B Cell Lymphoma\|Lymphoma, Non-Hodgkin	Adicet Bio, Inc	Phase 1
NCT04430530	4SCAR-T Therapy Post CD19-targeted Immunotherapy	Recruiting	CD19 Negative B-cell Malignancies	Shenzhen Geno-Immune Medical Institute\|ShiJiaZhuang Zhongxi Children Hospital\|Shenzhen Children's Hospital\|The Seventh Affiliated Hospital of Sun Yat-sen University	Phase 1\|Phase 2
NCT04186520	CAR-20/19-T Cells in Patients With Relapsed Refractory B Cell Malignancies	Recruiting	Non Hodgkin Lymphoma (NHL)\|Mantle Cell Lymphoma (MCL)\|Chronic Lymphocytic Leukemia (CLL)\|Follicular Lymphoma\|Marginal Zone Lymphoma\|Diffuse Large B Cell Lymphoma\|Primary Mediastinal Large B-cell Lymphoma (PMBCL)	Medical College of Wisconsin	Phase 1\|Phase 2
NCT04989803	Study Evaluating the Safety and Efficacy of KITE-363 in Participants With Relapsed and/or Refractory B-cell Lymphoma	Recruiting	Relapsed and/or Refractory B-cell Lymphoma	Kite, A Gilead Company\|Gilead Sciences	Phase 1
NCT03664635	MB-CART20.1 Lymphoma	Active, not recruiting	Relapsed or Refractory B-cell Non-Hodgkin's Lymphoma\|Non-Hodgkin's Lymphoma\|B-cell Lymphoma Refractory\|B-cell Lymphoma Recurrent	Miltenyi Biomedicine GmbH	Phase 1\|Phase 2
NCT03893019	MB-CART20.1 Melanoma	Recruiting	Melanoma (Skin)	Miltenyi Biomedicine GmbH\|DLR German Aerospace Center	Early Phase 1
NCT05618041	The Safety and Efficacy Investigation of CAR-T Cell Therapy for Patients With Hematological Malignancies	Recruiting	Acute Lymphoblastic Leukemia\|Lymphoma\|Multiple Myeloma	Hebei Senlang Biotechnology Inc., Ltd.	Not Applicable
NCT03277729	A Phase I/II Study to Evaluate the Safety of Cellular Immunotherapy Using Autologous T Cells Engineered to Express a CD20-Specific Chimeric Antigen Receptor for Patients With Relapsed or Refractory B Cell Non-Hodgkin Lymphomas	Recruiting	Recurrent B-Cell Non-Hodgkin Lymphoma\|Recurrent Chronic Lymphocytic Leukemia\|Recurrent Diffuse Large B-Cell Lymphoma\|Recurrent Follicular Lymphoma\|Recurrent Lymphoplasmacytic Lymphoma\|Recurrent Mantle Cell Lymphoma\|Recurrent Marginal Zone Lymphoma\|Refractory B-Cell Non-Hodgkin Lymphoma\|Refractory Diffuse Large B-Cell Lymphoma\|Refractory Follicular Lymphoma\|Refractory Lymphoplasmacytic Lymphoma\|Refractory Mantle Cell Lymphoma\|Refractory Transformed Non-Hodgkin Lymphoma\|Recurrent Transformed B-Cell Non-Hodgkin Lymphoma\|Recurrent Transformed Chronic Lymphocytic Leukemia\|Refractory Marginal Zone Lymphoma\|Refractory Transformed B-Cell Non-Hodgkin Lymphoma\|Refractory Transformed Chronic Lymphocytic Leukemia\|Recurrent Small Lymphocytic Lymphoma\|Refractory Chronic Lymphocytic Leukemia\|Refractory Small Lymphocytic Lymphoma\|Recurrent Central Nervous System Lymphoma\|Refractory Central Nervous System Lymphoma	Fred Hutchinson Cancer Center\|Mustang Bio	Phase 1\|Phase 2
NCT04283006	A Study of CD20/CD22 Targeted CAR T-cell Therapy for Relapsed or Refractory Lymphoid Malignancies	Recruiting	Relapsed and Refractory\|Lymphoid Hematological Malignancies	He Huang\|Yake Biotechnology Ltd.\|Zhejiang University	Early Phase 1
NCT05421663	A Study of C-CAR039 in Patients With Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma	Recruiting	B Cell Non-Hodgkin's Lymphoma	Cellular Biomedicine Group, Inc.\|City of Hope Medical Center	Phase 1
NCT05418088	Genetically Engineered Cells (Anti-CD19/CD20/CD22 CAR T-cells) for the Treatment of Relapsed or Refractory Lymphoid Malignancies	Recruiting	Recurrent Acute Lymphoblastic Leukemia\|Recurrent B Acute Lymphoblastic Leukemia\|Recurrent B-Cell Prolymphocytic Leukemia\|Recurrent Chronic Lymphocytic Leukemia\|Recurrent High Grade B-Cell Lymphoma\|Recurrent Indolent Non-Hodgkin Lymphoma\|Recurrent Non-Hodgkin Lymphoma\|Recurrent Transformed Chronic Lymphocytic Leukemia\|Refractory Acute Lymphoblastic Leukemia\|Refractory B Acute Lymphoblastic Leukemia\|Refractory B-Cell Prolymphocytic Leukemia\|Refractory Chronic Lymphocytic Leukemia\|Refractory High Grade B-Cell Lymphoma\|Refractory Indolent Non-Hodgkin Lymphoma\|Refractory Non-Hodgkin Lymphoma\|Refractory Transformed Chronic Lymphocytic Leukemia	Sumithira Vasu\|Ohio State University Comprehensive Cancer Center	Phase 1
NCT05149391	A Study of C-CAR039 in Subjects With Relapsed and/or Refractory B Cell Non-Hodgkin's Lymphoma	Recruiting	B Cell Non-Hodgkin's Lymphoma	Peking University\|Peking University Cancer Hospital & Institute	Phase 1
NCT04215016	Safety of Autologous Humanized Anti-CD19 and Anti-CD20 Dual Specific CAR-T Cells in Adult Patients With Diffuse Large B-cell Lymphoma	Recruiting	Relapsed or Refractory DLBCL Patients With Either CD19 or CD20 Positive	Fujian Medical University	Phase 1
NCT04049383	CAR-20/19-T Cells in Pediatric and Young Adult Patients With Relapsed/Refractory B Cell ALL	Recruiting	Acute Lymphoblastic Leukemia, in Relapse\|Acute Lymphoblastic Leukemia With Failed Remission\|Acute Lymphoblastic Leukemia Recurrent\|Acute Lymphoblastic Leukemia Not Having Achieved Remission\|Acute Lymphoblastic Leukemia, Pediatric\|Acute Lymphoblastic Leukemia	Medical College of Wisconsin\|Children's Hospital and Health System Foundation, Wisconsin	Phase 1
NCT04429438	Multi-CAR-T Cells Targeting B Cell Lymphomas	Recruiting	B Cell Lymphoma (BCL)	Shenzhen Geno-Immune Medical Institute\|The Seventh Affiliated Hospital of Sun Yat-sen University\|Shenzhen Children's Hospital	Phase 1\|Phase 2
NCT04889716	CAR-T Followed by Bispecific Antibodies	Recruiting	Large B-cell Lymphoma	Abramson Cancer Center of the University of Pennsylvania\|Genentech, Inc.	Phase 2
NCT04016129	CAR-T Immunotherapy Targeting CD19- ALL	Recruiting	B-cell Leukemia	Shenzhen Geno-Immune Medical Institute	Phase 1\|Phase 2
NCT05388695	To Observe the Dual-target Chimeric Antigen Receptor T Cells in the Treatment of B Cell Hematologic Tumors	Recruiting	19 and 22+ B Cell Hematologic Tumors\|19 and 20+ B Cell Hematologic Tumors	Hebei Senlang Biotechnology Inc., Ltd.\|Tongji Hospital	Phase 1
NCT03407859	Sequential Treatment With CD20/CD22/CD10-CART After CD19-CART Treatment Base on MRD in Relapsed/Refractory B-ALL	Recruiting	Therapy Related Leukemia	Zhujiang Hospital\|Nanfang Hospital of Southern Medical University	Early Phase 1
NCT05010564	CAR-T Cell, B-cell Acute Lymphoblastic Leukemia (TriCAR)	Not yet recruiting	Leukemia, B-Cell	Baylor College of Medicine\|Texas Children's Cancer Center	Phase 1
NCT05094206	CAR20.19.22 T-cells in Relapsed, Refractory B-cell Malignancies	Recruiting	B-cell Non Hodgkin Lymphoma\|B-cell Chronic Lymphocytic Leukemia	Medical College of Wisconsin\|Miltenyi Biomedicine GmbH	Phase 1
NCT04792489	DALY 2.0 USA/ MB-CART2019.1 for DLBCL	Recruiting	DLBCL	Miltenyi Biomedicine GmbH	Phase 2
NCT03870945	Safety of MB-CART2019.1 in Lymphoma Patients (MB-CART2019.1 Lymphoma / DALY 1)	Active, not recruiting	B-cell Non Hodgkin Lymphoma	Miltenyi Biomedicine GmbH\|ICON plc	Phase 1\|Phase 2
NCT05292898	A Triple-targeted Cell Preparation Targeting CD19/CD20/CD22 in Patients With Relapsed/Refractory B-cell Acute Lymphocytic Leukemia	Recruiting	Acute Lymphocytic Leukemia	Institute of Hematology & Blood Diseases Hospital\|Nanjing Legend Biotech Co.	Phase 1
NCT04074330	A Study of TAK-981 Given With Rituximab in Adults With Relapsed or Refractory CD20-Positive Non-Hodgkin Lymphoma	Active, not recruiting	Lymphoma, Non-Hodgkin	Takeda	Phase 1\|Phase 2
NCT05169489	A Study of bbT369 in Relapsed and/or Refractory B Cell Non-Hodgkin's Lymphoma (NHL)	Recruiting	Diffuse Large B Cell Lymphoma (DLBCL)	2seventy bio	Phase 1\|Phase 2
NCT04844866	Efficacy and Safety of MB-CART2019.1 vs. SoC in Lymphoma Patients	Recruiting	Diffuse Large B-cell Lymphoma	Miltenyi Biomedicine GmbH\|ICON plc	Phase 2
NCT05318963	Targeting CD19/CD20/CD22 Triple-targeted Cell in Patients With Relapsed/Refractory B-cell Lymphoma	Recruiting	B-cell Lymphoma Recurrent\|B-cell Lymphoma Refractory	Qiu Lugui\|Nanjing Legend Biotech Co.\|Institute of Hematology & Blood Diseases Hospital	Phase 1
NCT05379647	Natural Killer (NK) Cell Therapy for B-Cell Malignancies	Recruiting	B-cell Lymphoma\|B-cell Acute Lymphoblastic Leukemia	Zhejiang University\|Hangzhou Qihan Biotech Co., Ltd.	Phase 1

References

Du, Jiamu, et al. "Structure of the Fab fragment of therapeutic antibody Ofatumumab provides insights into the recognition mechanism with CD20." Molecular immunology 46.11-12 (2009): 2419-2423.
Kumar, Anand, et al. "Binding mechanisms of therapeutic antibodies to human CD20." Science 369.6505 (2020): 793-799.
Therapeutic CD20-Targeting Antibodies Differ in Their Binding Modes. Cancer Discov. 2020;10 (10):OF6.
JCO Flashback : Evaluating Chimeric Anti-CD20 Monoclonal Antibody Therapy for Relapsed B-cell Lymphoma (1998). J Clin Oncol. 2023;41 (2):153.
Shah, Nirav N., et al. "Bispecific anti-CD20, anti-CD19 CAR-T cells for relapsed B cell malignancies: a phase 1 dose escalation and expansion trial." Nature medicine 26.10 (2020): 1569-1575.
Larson, Sarah M., et al. "CD19/CD20 bispecific chimeric antigen receptor (CAR) in naive/memory T cells for the treatment of relapsed or refractory non-Hodgkin lymphoma." Cancer Discovery 13.3 (2023): 580-597.
Chen, Zhaoqi, et al. "Loop CD20/CD19 CAR-T cells eradicate B-cell malignancies efficiently." Science China Life Sciences 66.4 (2023): 754-770.