Teclistamab in multiple myeloma: mechanism, structure and clinical trial results

Author: Alisha GC

Teclistamab is a first-in-class bispecific antibody directed against B-cell maturation antigen (BCMA) and CD3 that has significantly improved the treatment of relapsed or refractory multiple myeloma (RRMM). By simultaneously binding malignant plasma cells and cytotoxic T lymphocytes, Teclistamab redirects endogenous T cells to eliminate BCMA-expressing tumor cells through major histocompatibility complex (MHC)-independent immune activation. This mechanism circumvents limitations associated with conventional chemotherapy and antigen-restricted immunotherapies. Clinical trials have shown significant response rates in heavily pretreated multiple myeloma patients, including individuals resistant to proteasome inhibitors, immunomodulatory drugs, and anti-CD38 monoclonal antibodies. However, therapeutic resistance driven by antigen downregulation, T-cell exhaustion and tumor microenvironment-mediated immune suppression remains a significant challenge. This review provides an in-depth analysis of Teclistamab’s molecular architecture, immunological mechanism of action, pharmacokinetics, clinical efficacy, resistance pathways and new strategies designed to improve therapeutic durability.

Teclistamab is one humanized bispecific IgG4 monoclonal antibody designed to bind simultaneously:

This double bond configuration enables direct immune synapse formation between T cells and tumor cells, triggering targeted cytotoxic responses.

Unlike less bispecific T-cell engaging (BiTE) molecules such as Blinatumomab, Teclistamab retains a modified Fc domainwhich improves structural stability and pharmacokinetic properties while minimizing unwanted immune activation.

Important structural features include:

• Full-length IgG-based bispecific antibody architecture

• Engineered Fc region with reduced Fcγ receptor binding

• Improved serum half-life compared to Fc-less bispecific antibodies

• Ability to subcutaneous administration

This design enables sustained therapeutic exposure while reducing the need for continuous infusion.

B-cell maturation antigen (BCMAalso known as TNFRSF17) is a transmembrane receptor belonging to tumor necrosis factor receptor (TNFR) superfamily. It is primarily expressed in:

BCMA plays a central role in plasma cell survival by binding the ligands:

Upon ligand engagement, BCMA activates intracellular signaling pathways that promote plasma cell proliferation and resistance to apoptosis.

Important downstream pathways include:

These pathways support the survival and expansion of myeloma cells in the bone marrow microenvironment.

From a therapeutic perspective, BCMA represents an ideal immunotherapy target because it shows:

• High expression in multiple myeloma cells

• Minimal expression in non-plasma cell tissues

• Essential role in plasma cell survival signaling

These properties allow selective targeting of malignant plasma cells while limiting off-target toxicity.

The other functional arm of Teclistamab binds CD3εa critical component of T-cell receptor (TCR) complex.

The CD3 complex consists of several subunits:

• CD3γ

• CD3δ

• CD3ε

• CD3ζ homodimers

The CD3ζ chains contain immunoreceptor tyrosine-based activation motifs (ITAMs) which initiates intracellular signaling following T-cell receptor engagement.

When Teclistamab binds CD3ε:

• Polyclonal T cells are recruited to tumor cells

• T cell receptor clustering occurs

• Intracellular signaling pathways are activated

Importantly, this process is happening regardless of antigen presentationwhich allows T cells to eliminate tumor cells even when major histocompatibility complex (MHC) expression is reduced or absent.

Teclistamab contains a modified IgG4 Fc region designed to optimize pharmacokinetic and safety profiles.

Important Fc modifications provide:

• Reduced binding to Fcγ receptors

• Reduced antibody-dependent cellular cytotoxicity (ADCC)

• Reduced complement activation

• Prolonged serum half-life (~3–4 days)

These functions activate intermittent subcutaneous dosing rather than continuous intravenous infusion.

1. Immunological synapse formation and redirection of T cells

Teclistamab works by physical linking of CD3-positive T cells to BCMA-expressing myeloma cellsthereby forming a functional cytotoxic immune synapse.

The process involves several sequential steps:

1. Teclistamab binds BCMA on malignant plasma cells.

2. The other binding arm engages CD3 on T cells.

3. Close cellular proximity induces T cell receptor clustering.

4. Cytotoxic granules are polarized towards the tumor cell interface.

This artificial synapse mimics physiological immune cell interactions and triggers T-cell activation.

Intracellular signal transduction

Following CD3 engagement, a cascade of intracellular signaling events occurs:

1. Lck kinase phosphorylates ITAMs on CD3ζ chains

2. ZAP-70 is recruited and activated

3. Adapter proteins included LAT and SLP-76 assemble signaling complexes

Downstream signaling pathways are then activated:

Calcium-calcineurin signaling → NFAT activation

Protein kinase C signaling → NF-κB activation

MAP kinase cascade → AP-1 transcriptional activation

Together, these transcriptional programs drive T cell activation, proliferation and cytotoxic activity.

Effector cytotoxic functions

Activated T cells eliminate tumor cells through several mechanisms:

Perforin-granzyme cytotoxicity

Perforin forms pores in tumor cell membranes, allowing granzyme B to enter and trigger apoptosis.

Cytokine release

Activated T cells release inflammatory cytokines such as:

These cytokines enhance immune activation and recruit additional immune cells.

Serial murder

A single activated T cell can disengage and sequentially destroy multiple tumor cells.

2. T-cell expansion and immune memory

In addition to immediate cytotoxic effects, Teclistamab promotes expansion of T-cell populations including:

These memory populations can contribute to long-term immune monitoring and sustained disease control.

Teclistamab exhibits favorable pharmacokinetic properties due to its IgG-based structure.

Key features include:

• Subcutaneous administration

• Half-life of approx 3-4 days

• Gradual T-cell activation with stepwise dosing

• Preferably expansion of CD8+ cytotoxic T cells

Step-up dosing protocols are implemented to reduce the risk of cytokine release syndrome.

MajesTEC-1 clinical trial

The MajesTEC-1 phase I/II trial evaluated Teclistamab in patients with heavily pretreated relapsed or refractory multiple myeloma.

Participants had previously received several therapy classes including:

Key clinical outcomes included:

• Overall Response Rate (ORR): ~63%

• Complete response or better: ~39%

• Median response time: ~18 months

These results show strong activity in patients with otherwise limited treatment options.

Despite its therapeutic effect, Teclistamab is associated with several immune-related side effects.

Cytokine Release Syndrome (CRS)

CRS is the most common toxicity and occurs due to rapid immune activation.

Symptoms may include:

Most cases are class 1–2 and manageable with supportive therapy or IL-6 blockade.

Infections

Teclistamab can reduce normal plasma cells, leading to:

Patients may require immunoglobulin replacement therapy.

Neurotoxicity

Immune effector cell-associated neurotoxicity syndrome (ICANS) may occur, but less frequently than with CAR-T therapy.

Symptoms may include:

• Confusion

• Aphasia

• Seizures (rare)

1. Loss or downregulation of BCMA antigen

Tumor cells can evade immune targeting by reducing BCMA expression through:

Loss of surface antigen reduces antibody binding and recruitment of T cells.

2. T-cell exhaustion

Chronic immune stimulation can lead to dysfunctional T cells characterized by:

• Upregulation of inhibitory receptors (PD-1, TIM-3, LAG-3)

• Reduced cytokine production

• Reduced chemotherapy capacity

3. Immunosuppressive tumor microenvironment

The bone marrow microenvironment of multiple myeloma contains several immune suppressive components:

• Regulatory T cells (Tregs)

• Myeloid-derived suppressor cells (MDSCs)

• Immunosuppressive cytokines such as IL-10 and TGF-β

These factors impair effective T-cell responses.

Several therapeutic strategies are under investigation.

Bispecific antibodies with two targets

Targeting additional plasma cell antigens may reduce antigen escape.

Examples include:

Immune checkpoint inhibition

Combining Teclistamab with checkpoint inhibitors can restore exhausted T cells.

Potential combinations include:

• Anti-PD-1 antibodies

• Anti-PD-L1 therapies

Improves T-Cell Fitness

Strategies to improve T-cell persistence include:

• Cytokine treatment (IL-7, IL-15)

• Combination with immunomodulating drugs

• Adoptive cellular therapies

Both Teclistamab and CAR-T therapies target BCMA, but differ in their approach.

Teclistamab

• Off-the-shelf antibody treatment

• No genetic modification required

• Subcutaneous administration

CAR-T therapy

• Requires genetic engineering of the patient’s T cells

• Personalized production process

• Potentially lengthy responses

Each therapy provides unique benefits depending on clinical conditions.

Teclistamab represents a major advance in the immunotherapy of multiple myeloma by enabling potent BCMA-directed T-cell redirection. Its bispecific antibody design enables effective tumor killing independent of antigen presentation while maintaining favorable pharmacokinetic properties. Although challenges such as antigen escape, T-cell exhaustion, and immunosuppressive microenvironments remain, ongoing research into combination therapies and next-generation bispecific antibodies holds significant promise. Continued integration of molecular biology, immunology and clinical innovation will be crucial to optimize Teclistamab-based treatments and achieve lasting remissions in multiple myeloma.

Q1. What is Teclistamab?
Teclistamab is a bispecific antibody that targets BCMA on multiple myeloma cells and CD3 on T cells, enabling immune-mediated tumor killing.

Q2. Why is BCMA an important target in multiple myeloma?
BCMA is highly expressed on malignant plasma cells and plays a crucial role in signaling plasma cell survival.

Q3. What are the main side effects of Teclistamab?
Common side effects include cytokine release syndrome, infections, and occasional neurotoxicity.

Q4. How does Teclistamab differ from CAR-T therapy?
Teclistamab redirects existing T cells using an antibody, while CAR-T therapy involves genetically modifying the patient’s T cells.

Q5. What causes resistance to Teclistamab?
Resistance may arise from loss of BCMA antigen, exhaustion of T cells, or immunosuppressive factors in the tumor microenvironment.