August 2025: Immune Cell Engagers: Next-Generation Immunotherapy

Immune cell engagers (ICEs) are engineered molecules that redirect endogenous immune effector cells toward malignant targets by forming synthetic immune synapses. These agents offer a mechanism of tumor cell elimination that is independent of antigen processing and presentation via the major histocompatibility complex (MHC). By directly linking immune effector cells, such as T cells, natural killer (NK) cells, or phagocytic cells, with tumor-associated antigens (TAAs) on the surface of cancer cells, ICEs bypass several immune evasion strategies frequently observed in tumors, such as MHC downregulation or loss of antigen presentation machinery.

Most ICEs are constructed as bispecific antibodies (bsAbs), typically composed of two single-chain variable fragments (scFvs): one targeting a TAA and the other targeting an activation receptor on the effector immune cell. The resulting artificial immune synapse facilitates targeted immune activation and cytolysis. ICEs represent a scalable, off-the-shelf alternative to personalized adoptive cell therapies.

Types of Immune Cell Engagers

A recent review classifies ICEs based on the immune effector cell population they are designed to engage.

T Cell Engagers (TCEs):

• Typically constructed as bispecific T cell engagers (BiTEs) linking a TAA-specific scFv to an anti-CD3ε scFv.

• Promote the formation of an immunological synapse between T cells and tumor cells, inducing TCR signaling cascades.

• Trigger release of cytotoxic granules (perforin and granzyme) from both CD8+ and CD4+ T cells, leading to tumor cell apoptosis.

• May induce cytokine production and T cell proliferation, contributing to durable responses.

• Co-stimulatory molecules such as CD28 or 4-1BB can be targeted in trispecific formats to enhance activation and persistence.

NK Cell Engagers (NKCEs):

• Target innate immune NK cells, which lack TCR/CD3 complexes but express activating receptors like CD16 (FcγRIII) and NKG2D.

• CD16 is the most widely used receptor in NKCEs due to its capacity to trigger antibody-dependent cellular cytotoxicity (ADCC).

• CD16-targeted ICEs have demonstrated efficacy in hematological malignancies and early clinical success (e.g., AFM13 in Hodgkin lymphoma).

• Engagement of NKG2D provides an alternative activation pathway and has shown preclinical activity against HER2- and CEA-positive tumors.

• Induce cytokine and chemokine production, contributing to immune modulation of the tumor microenvironment.

Cytotoxic/Phagocytic Cell Engagers:

• Designed to engage monocytes, macrophages, dendritic cells, or activated neutrophils via CD64 (FcγRI), a high-affinity IgG receptor.

• BsAbs targeting CD64 and a TAA enable antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis.

• Preclinical data demonstrate tumor cell lysis in HER2- and EpCAM-expressing tumor models.

• Expand the immune effector repertoire beyond lymphoid cells, offering potential synergies with macrophage-mediated remodeling of the tumor microenvironment.

A recent analysis of 91 research articles published from 2019-2025 on immune cell engagers revealed that T cell engagers (TCEs) dominate the field, comprising 51.6% of studies. NK cell engagers (NKCEs) account for 41.8%, reflecting rising interest in innate immune strategies. Phagocyte cell engagers (PCEs) remain less explored, representing 6.6% of publications, but indicate emerging therapeutic potential.

Recent Advances in T Cell Engagers (TCEs)

Innovations in molecular design, such as 1+1 (bivalent binding), 2+1 (increased avidity), and 1+1+1 (trispecific) formats, have optimized tumor targeting while reducing systemic toxicity. Current research focuses on improving half-life, minimizing cytokine release syndrome (CRS), and expanding the range of targetable antigens through TCR-like modalities. TCE applications are also extending into non-oncologic fields, supported by AI-guided design tools that enhance specificity, stability, and manufacturability.

FDA Approval – Linvoseltamab-gcpt (Lynozyfic) by Regeneron | July 2, 2025

• A BCMA × CD3 bispecific TCE for adult patients with relapsed or refractory multiple myeloma after ≥4 prior therapies that works by binding BCMA on myeloma cells and CD3 on T cells to redirect cytotoxicity.

Acquisition – ISB 2001 by AbbVie | July 10, 2025

• A trispecific antibody targeting CD38, BCMA, and CD3 with indication for multiple myeloma, developed by Ichnos Glenmark Innovation (IGI), was bought by AbbVie with $700M upfront. Adding CD38 aims to improve binding in tumors with low BCMA and mitigate resistance via antigen escape

Acquisition – DR-0201 by Sanofi | March 20, 2025

• A bispecific myeloid cell engager (MCE), CD20-directed and indicated for refractory B-cell-mediated autoimmune diseases, was developed by Dren Bio, Inc.. Sanofi to pay $600M upfront. It engages tissue-resident and trafficking myeloid cells to mediate targeted phagocytosis and deep B-cell depletion.

Research – E1-DHFR2-αCD3 TCE

• Format: EGFR × CD3 bifunctional fusion protein with modular assembly

• Design: Fusion of EGFR-binding fibronectin (E1) and anti-CD3 scFv on DHFR2 scaffold

• Mechanism: Multivalent nanoring assembly via bis-methotrexate enables tumor and T cell engagement

Research – eFab TCE

• Format:  HER2 × HER3 × CD3 trispecific antibody

• Design: One Fab and two eFab arms with divergent hetEHD2 domain architecture

• Function: Simultaneously binds three targets and induces T cell-mediated cytotoxicity in HER2/HER3+ cancer models

Recent Advances in NK Cell Engagers (NKCEs)

Compared to T cells, NK cells exhibit a reduced propensity for cytokine release, including tumor necrosis factor (TNF), due to higher activation thresholds and limited intracellular trafficking of cytokines. This intrinsic property contributes to a lower risk of cytokine release syndrome (CRS), a major limitation of T cell engager (TCE) therapy. NKCEs, including bispecific (BiKEs) and trispecific (TriKEs) formats, activate NK cells by engaging surface receptors such as CD16a and NKG2D. Next-generation NKCEs incorporate interleukin-2 (IL-2) or IL-15 moieties to enhance persistence and cytotoxicity. Comparative studies in animal models have demonstrated that NKCEs can offer distinct therapeutic advantages over TCEs, particularly in immune-cold tumor environments, suggesting their potential as standalone or combinatorial strategies in oncology.

Phase I – XB628 bispecific NKCE by Invenra and Exelixis

• Format: Bispecific NK cell engager targeting NKG2A (inhibitory receptor on NK cells) and PD-L1 (immune checkpoint ligand on tumor cells)

• Mechanism: Dual checkpoint blockade approach to enhance NK cell activation in the tumor microenvironment

• Indication: Advanced or metastatic solid tumor

Preclinical Development – B7-H3 TriKE

• Format: Trispecific molecule for NK cell activation

• Design: CD16-binding camelid nanobody, IL-15 moiety, B7-H3-binding nanobody

• Mechanism: Enhances NK cell cytotoxicity in hypoxic tumor microenvironment, with implications of overcoming TME immunosuppression in head and neck squamous cell carcinoma (HNSCC)

Preclinical Development – PD-1 × CD16 BiKE

• Format: IgG-like bispecific killer engager (BiKE)

• Targets: Programmed death-1 (PD-1) on T cells and CD16 on NK cells

• Mechanism: Redirects NK cells to eliminate PD-1+ immune effector cells, including activated T cells

Research – HER2 × NKp30 × IL-15RαSu TriKE

• Format: Trispecific NK cell engager with integrated cytokine support

• Targets: HER2 (tumor antigen), NKp30 (activating NK receptor), and IL-15Rα (cytokine receptor)

• Design: Incorporates a modified IL-15 (N72D) fused to IL-15Rα sushi domain to enhance NK expansion