CD37 Chimeric Antigen Receptor (CAR): A Comprehensive Guide and Our Service & Product Introduction

CD37, a member of the tetraspanin (transmembrane 4 superfamily) cell surface glycoprotein, is a highly specific tumor-associated antigen (TAA) widely expressed in various hematological malignancies, especially B-cell lymphomas and some T-cell lymphomas. As an alternative and complementary target to CD19 and CD20, CD37 has become a promising focus in chimeric antigen receptor (CAR) immunotherapy research. RGBiotech is committed to providing high-quality CD37 CAR expression plasmid vectors and professional custom vector construction services, supporting researchers and biopharmaceutical enterprises in accelerating the development of CD37-targeted CAR-T/CAR-NK therapies. Please contact us at admin@rgbiotech.com for more information.

Our CD37 CAR Expression Plasmid Vector Products and Custom Services

RGBiotech provides a full range of CD37 CAR expression plasmid vectors, covering 1st to 5th generation CARs, with diverse vector backbones and rich functional modifications, to meet the needs of different research stages (in vitro experiments, in vivo animal models, preclinical trials). At the same time, we provide professional custom plasmid vector construction services, tailoring personalized solutions according to your research needs, accelerating your research progress. Our products include lentiviral vectors (e.g., pLenti-CMV-CD37-GFP-Puro), retroviral vectors, AAV vectors, non-viral vectors, and in vitro transcription (IVT) vectors for CAR mRNA production, supporting various experimental requirements for CD37 CAR research.

RGBiotech provides CD37 CAR expression plasmid vectors covering all generations (1st to 5th), meeting different research needs and application scenarios, including basic research and preclinical trials.
1) 1st Generation CD37 CAR: Only contains the CD3ζ intracellular signal domain. It can mediate the activation of T cells and kill CD37-positive tumor cells, but lacks co-stimulatory signals, resulting in weak T cell proliferation ability, short survival time, and limited anti-tumor efficacy. Suitable for preliminary research on CD37 targeting.
2) 2nd Generation CD37 CAR: Adds one co-stimulatory domain (CD28 or 4-1BB) based on the 1st generation. CD28 co-stimulation enhances T cell activation and proliferation, while 4-1BB co-stimulation improves T cell persistence and memory formation, significantly enhancing anti-tumor efficacy. This generation is widely used in current CD37 CAR research, with lentiviral vectors often used for stable expression under the control of the EF1α or CMV promoter.
3) 3rd Generation CD37 CAR: Contains two co-stimulatory domains (e.g., CD28+4-1BB, CD28+OX40, 4-1BB+OX40). It integrates the advantages of different co-stimulatory signals, further enhancing T cell activation, proliferation, persistence, and anti-tumor activity, and is suitable for the treatment of refractory and relapsed CD37-positive hematological malignancies.
4) 4th Generation CD37 CAR (Armored CAR): On the basis of the 3rd generation, it is engineered to express cytokines (IL-12, IL-15, IL-18) or immune checkpoint inhibitors (PD-1 scFv, CTLA-4 scFv). It can remodel the tumor microenvironment, overcome immune suppression, and enhance the anti-tumor effect of CAR-T cells. For example, CD37 CAR-T cells co-expressing IL-15 can improve persistence and anti-tumor activity in AML models.
5) 5th Generation CD37 CAR (Universal CAR): Optimized for off-the-shelf therapy, including allogeneic CAR-T cells (edited by CRISPR/Cas9 to knock out TCR or HLA genes) and universal CAR structures (e.g., bispecific CAR, switchable CAR). It solves the problem of donor shortage and reduces the risk of graft-versus-host disease (GVHD), accelerating the clinical transformation of CD37 CAR therapy. Notably, CD37 CAR-T cells do not exhibit significant fratricide, making them suitable for allogeneic development.

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Introduction of CD37

CD37 is encoded by the CD37 gene (NCBI Gene ID: 951; Uniprot ID: P11049; OMIM: 151520), also known as GP52-40 or TSPAN26. Located on human chromosome 19p13.11 (chr 19: 17,956,287–17,973,443 bp), the CD37 gene spans approximately 17.2 kb, contains 8 exons, and encodes a 298-amino-acid transmembrane glycoprotein. As a highly conserved gene across vertebrates, CD37 is primarily expressed in immune cells, with its sequence and functional domains highly conserved, laying a solid foundation for cross-species research and preclinical trials. Alternate splicing results in multiple transcript variants encoding different isoforms, which may play distinct roles in physiological and pathological processes.

CD37 is a cell surface glycoprotein belonging to the tetraspanin superfamily, characterized by four hydrophobic transmembrane domains, with a molecular weight of approximately 40–52 kDa (mature glycosylated form). Its structure consists of three core functional domains that determine its biological activity and antigenicity.
1) Extracellular domain: Contains two extracellular loops (small and large), with the large extracellular loop (LEL) serving as the main antigenic epitope and binding site for CAR single-chain variable fragments (scFv). This domain also mediates interactions with other tetraspanins, integrins, and signaling molecules, participating in membrane organization and signal transduction.
2) Transmembrane domain: Four hydrophobic transmembrane segments that anchor the protein to the cell membrane, forming a characteristic tetraspanin structure. This domain is critical for maintaining the stability of CD37 on the cell surface and mediating its interaction with other membrane proteins.
3) Cytoplasmic domain: Short N-terminal and C-terminal cytoplasmic tails that lack intrinsic enzymatic activity but can recruit adaptor proteins (e.g., PI3K, SHP1) to mediate downstream signaling pathways, regulating cell survival, proliferation, and adhesion.

CD37 is a multifunctional immune regulatory protein primarily involved in immune cell activation, adhesion, migration, and survival, playing a crucial role in physiological immune responses and pathological processes such as tumor progression:
1) Immune cell regulation: It is predominantly expressed on mature B cells, with low levels of expression on T cells, NK cells, monocytes, and dendritic cells. CD37 regulates B-cell activation, proliferation, and differentiation, and is critical for normal plasma cell development by clustering VLA-4 (α4β1 integrin) on germinal center B cells to activate AKT signaling. It also participates in T-cell-B-cell interactions and dendritic cell migration by controlling CLEC-2 membrane organization.
2) Signal transduction: Through its cytoplasmic tails, CD37 recruits adaptor proteins to activate downstream signaling pathways such as PI3K/AKT and SHP1, mediating both pro-survival and pro-apoptotic signals. Ligation of CD37 by targeted peptides can induce AKT activation (pro-survival) and SHP1 signaling (pro-apoptotic), with cellular death being the predominant outcome.
3) Tumor progression: In B-cell malignancies, CD37 overexpression confers proliferative and anti-apoptotic advantages to tumor cells, and its expression level is associated with disease aggressiveness and poor prognosis in some cases (e.g., acute myeloid leukemia). However, CD37 mutations (predominantly in immune-privileged site-associated diffuse large B-cell lymphoma) can lead to loss of function, impairing CD37 protein expression on the tumor cell membrane.
4) Adhesion and migration: CD37 mediates cell-cell and cell-matrix adhesion by interacting with integrins and other tetraspanins, promoting the homing and infiltration of immune cells and tumor cells into lymphoid tissues.

CD37 has a relatively restricted tissue distribution, with distinct expression patterns in normal and tumor tissues, providing a favorable safety window for targeted immunotherapy. Notably, CD37 is not found in non-hematologic tissues, making it a highly specific target for hematological malignancies.
1) Normal tissues: Biased expression in lymphoid tissues, including lymph nodes (RPKM 111.7) and spleen (RPKM 99.3), with high expression on mature B cells (15 times higher than other immune cells) and low levels on T cells, NK cells, monocytes, dendritic cells, and plasma cells. It is not expressed in non-hematopoietic tissues such as liver, kidney, heart, or skin.
2) Tumor tissues: High and specific expression in a variety of hematological malignancies, including B-cell non-Hodgkin lymphoma (B-NHL), chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), follicular lymphoma, diffuse large B-cell lymphoma (DLBCL), Burkitt’s lymphoma, and some cutaneous and peripheral T-cell lymphomas (CTCL, PTCL). It is also expressed on acute myeloid leukemia (AML) blasts, with expression correlating with ELN 2017 risk stratification. CD37 expression is low or absent in acute lymphoblastic leukemia (ALL) and multiple myeloma.

CD37 is closely associated with the occurrence, development, and prognosis of multiple hematological malignancies, and its expression pattern makes it a promising therapeutic target.
1) Hematological malignancies: B-cell non-Hodgkin lymphoma (B-NHL) - CD37 is highly expressed in most subtypes, including DLBCL, MCL, and follicular lymphoma, with mutations exclusively identified in immune-privileged site-associated DLBCL. Chronic lymphocytic leukemia (CLL) - CD37 expression is associated with disease aggressiveness, and its deficiency in CLL mouse models leads to decreased survival. Acute myeloid leukemia (AML) - CD37 is expressed on most primary AML blasts, serving as a safe target for CAR-T therapy. Cutaneous and peripheral T-cell lymphomas (CTCL, PTCL) - CD37 is expressed in some cases, and these patients have a poor prognosis, making CD37 CAR-T a potential therapeutic option.
2) Immune-related diseases: Although primarily associated with malignancies, CD37 is involved in immune regulation, and its deficiency can impair dendritic cell migration and anti-tumor immunity, potentially contributing to autoimmune diseases or chronic inflammatory disorders.

Introduction of CD37 Chimeric Antigen Receptor (CAR)

CD37 CAR is a chimeric antigen receptor specifically targeting the CD37 antigen, engineered to express on the surface of immune cells (T cells, NK cells) through plasmid vectors. It enables immune cells to specifically recognize and kill CD37-positive tumor cells in a major histocompatibility complex (MHC)-independent manner, overcoming the limitations of CD19 CAR-T therapy (e.g., antigen loss and relapse). The core structure of CD37 CAR consists of four parts: extracellular antigen-binding domain (anti-CD37 scFv), hinge region (e.g., CD8α hinge), transmembrane domain (e.g., CD8α or CD28 transmembrane domain), and intracellular signal domain. Different generations of CARs are distinguished by the number and type of intracellular signal domains, with distinct functional characteristics adapted to different research and application scenarios. A typical second-generation CD37 CAR consists of anti-CD37 scFv linked to CD8 hinge/transmembrane domain and 4-1BB/CD3ζ signaling domains, which has shown potent anti-tumor activity in preclinical models.

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