Immunotherapy Target: CD19 Antigen

Immunotherapy Target: CD19 Antigen

By Mallory Griffin

CD19 remains a hot target in immunotherapy, driving innovation across a range of diseases. This is evidenced by recent approvals for new treatments in multiple sclerosis and leukemia and a major acquisition in the bispecific antibody space:  

September 9, 2024: Zenas acquired clinical trial approval from the Center for Drug Evaluation (CDE) of the China National Medical Products Administration for Obexelimab injection, a new class 1 drug from Xencor, to treat adult relapsing multiple sclerosis (RMS).

August 9, 2024: Merck, through a subsidiary, acquired Tongren Biopharma’s CD3×CD19 bispecific antibody CN201 pipeline for $1.3 billion.

February 28, 2024: The CDE approved AstraZeneca’s CD19 bispecific antibody AZD0486 for treating relapsed or refractory B-cell acute lymphoblastic leukemia (r/r B-ALL).

Cluster of Differentiation 19 (CD19)

B-lymphocyte antigen CD19, also known as Cluster of Differentiation 19 (CD19), is a membrane protein expressed on all B cell lineages, malignant B cells, and follicular dendritic cells. However, hematopoietic stem cells, plasma cells, T cells, or other tissues, do not express CD19, which gives it a unique expression profile. The extracellular domain of CD19 has two C2-type Ig-like domains, while the intracellular C-terminal domain has multiple tyrosine residues, with Y391, Y482, and Y513 being essential to its biological function (Figure 1).

Structure of CD19 protein.

Figure 1. CD19 structure [1]. 

CD19 plays a crucial role in B cell proliferation, differentiation, activation, and antibody production. It forms a signal transduction complex with CD21, CD81, and CD225, regulating both B Cell Receptor (BCR)-dependent and -independent signaling, which drives autoantibody production and immune-mediated damage (Figure 2).

B Cell Receptor (BCR) signaling pathways

Figure 2. B Cell Receptor (BCR) signaling pathways [2]. 

CD19 Antibody Drugs

CD19’s expression in most B-cell malignancies makes it an ideal target for lymphoma treatments. Four antibody drugs targeting CD19 are currently on the market: one bispecific antibody (Blinatumomab), two monoclonal antibodies (Inebilizumab, Tafasitamab), and one ADC (Loncastuximab Tesirine), with more entering clinical trials. Common indications include diffuse large B-cell lymphoma (DLBCL), acute lymphoblastic leukemia (ALL), B-cell lymphoma, and follicular lymphoma (FL), with recent expansion into autoimmune inflammatory diseases.

Monoclonal Antibodies

The monoclonal antibody Obexelimab, developed by Xencor, uses an IgG4 design to bind both CD19 and FcγRIIb, inhibiting B cell function rather than depleting cells. This reduces side effects associated with cell lysis, with lower immunogenicity and a longer half-life. In November 2021, Zenas obtained global rights to Obexelimab from Xencor and plans to advance clinical research in IgG4-related diseases (IgG4-RD) and other autoimmune diseases. In September 2023, Zenas entered a strategic licensing and collaboration agreement with BMS, granting exclusive rights in Japan, South Korea, Taiwan, Singapore, Hong Kong, and Australia. Obexelimab is currently in phase 3 trials for warm autoimmune hemolytic anemia and IgG4-RD, highlighting CD19’s value in autoimmune disease.

Obexelimab mechanism of action

Figure 3. Obexelimab mechanism of action [3]. 

Bispecific Antibodies

AstraZeneca’s AZD0486, featuring a low-affinity anti-CD3 fragment and a silenced Fc, minimizes cytokine release and prevents non-specific toxicity. Clinical trials show an ORR of 81.2% in B-cell non-Hodgkin lymphoma (B-NHL) and 75% in DLBCL. On the other hand, Roche’s Englumafusp alfa, takes a different approach by simultaneously targeting CD19 and 4-1BB, triggering potent co-stimulation to sustain immune cell activity and enhance efficacy.

Structure of Englumafusp alfa

Figure 4. Structure of Englumafusp alfa [4]. 

Antibody-Drug Conjugates (ADC)

In addition to the marketed Loncastuximab Tesirine (Zynlonta), several Antibody-Drug Conjugates (ADCs) are under clinical investigation, including Sanofi and ImmunoGen’s Coltuximab ravtansine, Seagen’s Denintuzumab mafodotin, and AbbVie’s ABBV-319, each with unique payload and linker designs.

Summary of Antibody Drugs Targeting CD19

Company Drug Name Target or conjugate
Stage Indications
Monoclonal Antibodies (mAb)
Viela Bio / Horizon Therapeutics / Amgen Inebilizumab CD19 Approved June 2020 Neuromyelitis optica spectrum disorder
Incyte Tafasitamab-cxix CD19 Approved July 2020 Relapsed or refractory diffuse large B-cell lymphoma
Zenas / Xencor / BMS
Obexelimab
CD19 and Fc gamma receptor IIb
Phase 3
Warm autoimmune hemolytic anemia
IgG4-related disease
BMS
MDX-1342
CD19
Discountinued after Phase I
Chronic lymphocytic leukemia
Rheumatoid arthritis
IASO Biotherapeutics IASO-782 CD19 Phase 1 Autoimmune thrombocytopenia, warm autoimmune hemolytic anemia
Bispecific Antibodies (bsAb)
Amgen Blinatumomab CD19 / CD3 Approved December 2014 Philadelphia chromosome-negative relapsed or refractory B-cell precursor acute lymphoblastic leukemia, indolent B-cell lymphoma
TeneoTwo / AstraZeneca AZD0486 CD19 / CD3 Phase 3 Untreated follicular lymphoma
Curon Biopharmaceutical / Merck CN201 CD19 / CD3 Phase 1b / 2 Acute lymphoblastic leukemia
Roche Englumafusp alfa CD19 / 4-1BB Phase 1 / 2 Relapsed or refractory non-Hodgkin's lymphoma
Lüzhu Biotechnology K193 CD19 / CD3 Phase 1 Advanced solid tumors
ITabMed
A319
CD19 / CD3
Phase 1
Systemic lupus erythematosus
EVIVE Biotechnology Relapsed or refractory B-cell lymphoma
Antibody Drug Conjugates (ADC)
ADC Therapeutics Loncastuximab Tesirine CD19 with PBD conjugate Approved April 2021 Relapsed or refractory diffuse large B-cell lymphoma
Sanofi / ImmunoGen
Coltuximab ravtansine
CD19 with DM4 conjugate
Discountinued after Phase 2
Diffuse large B-cell lymphoma
Seagen
Denintuzumab mafodotin
CD19 with MMAF conjugate
Discountinued after Phase 2
Diffuse large B-cell lymphoma, grade 3b follicular lymphoma, transformed lymphoma
B-cell lymphoma, diffuse large B-cell lymphoma, grade 3b follicular lymphoma
Iksuda Therapeutics / LegoChem Biosciences LCB73 CD19 with PBD conjugate Phase 1 B-cell lymphoma, B-cell non-Hodgkin lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma
AbbVie ABBV-319 CD19 with Bromoacetamide conjugate Phase 1 Chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma
Fusion Proteins
GT Biopharma DT2219ARL CD19 / CD22 / DT390 Discontinued after Phase 1/2 Refractory B-lineage leukemia, Refractory B-lineage lymphoma, Relapsed B-lineage leukemia, Relapsed B-lineage lymphoma

Table 1. Antibody drugs targeting CD19 approved or in clinical trial. 

CD19 as a CAR-T Therapy Target

CD19-Targeting CAR-T Therapy for Hematologic Malignancies

CD19’s unique expression on B cell lineages makes it a prime target for chimeric antigen receptor-T cell therapies (CAR-T), which have shown groundbreaking success in treating B-cell malignancies like diffuse large B-cell lymphoma (DLBCL) and acute lymphoblastic leukemia (ALL). CAR-T therapies, such as Kymriah (tisagenlecleucel) and Yescarta (axicabtagene ciloleucel), specifically target CD19 on malignant B cells, redirecting the patient’s immune system to destroy these cancerous cells. Their success has catalyzed further developments in CAR-T therapies targeting CD19 and similar antigens, offering new hope for patients with relapsed or refractory blood cancers.

With the rapid advancements in CAR-T and other cellular therapies, CD19’s role in immunotherapy continues to expand. Clinical studies have demonstrated that targeting CD19 effectively induces remission in a substantial portion of patients with otherwise untreatable B-cell cancers. This success underscores CD19's enduring relevance in hematologic oncology and its role in driving forward the next generation of immunotherapies.

CD19-Targeting CAR-T Therapy for Autoimmune Disease

CD19-targeting CAR-T cell therapies are emerging as promising treatments for autoimmune diseases like systemic lupus erythematosus (SLE) and antisynthetase syndrome (ASS), providing new options for patients unresponsive to traditional immunosuppressive therapies. In SLE, a chronic disease marked by immune attacks on healthy tissues, CD19 CAR-T cell therapy has demonstrated rapid remission and enhanced quality of life in cases resistant to conventional treatments [5]. Similarly, a case study on ASS, which involves muscle inflammation and interstitial lung disease, reported complete clinical remission in a patient after CD19 CAR-T therapy, highlighting its potential to manage refractory cases [6]. These findings underscore the expanding applications of CD19 CAR-T therapies beyond cancer treatment, offering hope for individuals with challenging autoimmune disorders.

High Quality CD19 Proteins from KACTUS Available Off-the-Shelf

CD19 is advancing not only in hematologic cancers but also in autoimmune diseases, demonstrating significant therapeutic potential and market value. To support CD19-targeted drug development, KACTUS provides high-quality recombinant CD19 proteins. These proteins, expressed in mammalian cells, include multiple species and tag configurations, undergo rigorous quality testing, and are suitable for various applications such as animal immunization, antibody screening, and drug functionality validation.

Product Validation Data

Immobilized Human CD19, His Tag at 2 μg/ml (100 μl/Well) on the plate. Dose response curve for Coltuximab, hFc Tag with the EC50 of 5.3 ng/ml determined by ELISA.

Figure 5. Immobilized Human CD19, His Tag at 2 μg/ml (100 μl/Well) on the plate. Dose response curve for Coltuximab, hFc Tag with the EC50 of 5.3 ng/ml determined by ELISA.

Immobilized Human CD19, His Tag at 1 μg/ml (100 μl/well) on the plate. Dose response curve for Denintuzumab, hFc Tag with the EC50 of 2.1 ng/ml determined by ELISA.

Figure 6. Immobilized Human CD19, His Tag at 1 μg/ml (100 μl/well) on the plate. Dose response curve for Denintuzumab, hFc Tag with the EC50 of 2.1 ng/ml determined by ELISA.

Anti-CD19 Antibody, hFc Tag captured on CM5 Chip via Protein A can bind Cynomolgus/Rhesus macaque CD19, His Tag with an affinity constant of 0.46 μM as determined in SPR assay.

Anti-CD19 Antibody, hFc Tag captured on CM5 Chip via Protein A can bind Cynomolgus/Rhesus macaque CD19, His Tag with an affinity constant of 0.46 μM as determined in SPR assay.

CD19 Proteins Product List

Catalog No.

Product Description

Tag

Expression System

CD1-HM119

Human CD19

His Tag

HEK293

CD1-HMR102

Biotinylated Human CD19

His-Avi Tag

HEK293

CD1-CM119

Cynomolgus/Rhesus macaque CD19

His Tag

HEK293

CD1-MM119

Mouse CD19

His Tag

HEK293

CD1-HM119F

FITC-compatible Human CD19

His Tag

HEK293

References

[1] Tedder, T. F. (2009). CD19: A promising B cell target for rheumatoid arthritis. Nature Reviews Rheumatology, 5(10), 572-577. https://doi.org/10.1038/nrrheum.2009.184

[2] Aribi, M. (2020). Introductory Chapter: B-Cells. IntechOpen. doi: 10.5772/intechopen.90636

[3] https://investors.xencor.com/static-files/e704e415-b58a-430a-bfdb-8a04795178e9

[4] Tapia-Galisteo A, Álvarez-Vallina L, Sanz L. Bi- and trispecific immune cell engagers for immunotherapy of hematological malignancies. J Hematol Oncol. 2023 Jul 27;16(1):83. doi: 10.1186/s13045-023-01482-w.

[5] Rangel-Peláez, C., Martínez-Gutiérrez, L., Tristán-Manzano, M., Callejas, J. L., Ortego-Centeno, N., Martín, F., & Martín, J. (2024). CD19 CAR-T cell therapy: A new dawn for autoimmune rheumatic diseases? Frontiers in Immunology, 15, 1502712. https://doi.org/10.3389/fimmu.2024.1502712

[6] Taubmann, J., Knitza, J., Müller, F., Völkl, S., Aigner, M., Kleyer, A., Gary, R., Kretschmann, S., Boeltz, S., Atzinger, A., Kuwert, T., Roemer, F., Uder, M., Mackensen, A., & Schett, G. (2023). Rescue therapy of antisynthetase syndrome with CD19-targeted CAR-T cells after failure of several B-cell depleting antibodies. Rheumatology (Oxford, England), 63(1), e12. https://doi.org/10.1093/rheumatology/kead330

 

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