Resources>Antibody Industry Trends>Week 2, May 2025: Multifunctional NKCEs (Natural Killer Cell Engagers)

Week 2, May 2025: Multifunctional NKCEs (Natural Killer Cell Engagers)

Biointron 2025-05-13

Natural killer (NK) cell-based therapies are rapidly gaining traction as immunotherapies, offering advantages over traditional T cell-based approaches, particularly in safety and specificity. While T cell engagers (TCEs) have demonstrated clinical efficacy, their use is limited by toxicities such as cytokine release syndrome (CRS). In contrast, NK cells possess potent cytolytic capabilities with reduced pro-inflammatory cytokine production, making them ideal candidates for bispecific engager platforms. Recent studies have advanced our understanding of NK cell engager (NKCE) biology and demonstrated their potential in treating diverse and refractory malignancies.

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DOI: 10.1093/jimmun/vkaf036

Blueprint for Multifunctional NKCE Development

Recent comparative analyses have positioned NKCEs as a promising alternative to TCEs, particularly due to their lower propensity to trigger CRS. A study published in Cell Reports Medicine (Lin et al.) highlighted the mechanistic differences in tumor necrosis factor (TNF) production between NK and T cells, attributing NK cells' lower TNF secretion to reduced intracellular trafficking and processing. This foundational insight has enabled the design of NKCEs that co-engage activating receptors such as CD16 and NCR1, while incorporating interleukin-2 (IL-2) domains to sustain NK cell survival, proliferation, and cytotoxic function. 

These multifunctional NKCEs integrate features commonly associated with antibody therapeutics, such as engineered Fc regions for optimized binding and afucosylation to enhance antibody-dependent cellular cytotoxicity (ADCC). Benchmarking studies showed that NKCEs could be configured to bypass the limitations of receptor downregulation and low NK cell proliferation, inducing sustained tumor cell killing with reduced cytokine release. As a new class of antibody-derived therapeutics, multifunctional NKCEs offer modularity, specificity, and reduced immunotoxicity, establishing them as strong contenders for next-generation cancer immunotherapies.

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DOI: 10.1016/j.xcrm.2025.102117

NKCEs for Glioblastoma Therapy

Glioblastoma is a type of cancer that starts as a growth of cells in the brain or spinal cord. Traditional immunotherapies, including checkpoint inhibitors and T cell engagers, have demonstrated minimal efficacy in this context. In response, researchers at Purdue University have developed a novel antibody-based NKCE that is designed to simultaneously improve NK cell trafficking to glioblastoma lesions and mediate high-affinity tethering to tumor cells. The construct utilizes antibody scaffolding to engage NK cells through engineered Fc domains while targeting glioblastoma antigens. Notably, in vivo murine models demonstrated extended survival and enhanced intratumoral NK cell infiltration following treatment. Importantly, the platform supports off-the-shelf administration and can be integrated with both autologous and allogeneic NK cell products.

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Glioblastoma. Image credit: Mayo Clinic

Bispecific NK Cell Engagers Show Promising Clinical Outcomes in Refractory Lymphoma

Patients with CD30+ lymphomas refractory to brentuximab vedotin and anti-PD1 therapies face limited treatment options and poor prognoses. Addressing this unmet need, a phase 1 trial evaluated AFM13 (a bispecific antibody targeting CD30 and CD16A) in combination with cytokine-preactivated, cord blood-derived NK cells. The study assessed the safety, persistence, and clinical efficacy of this NKCE platform in heavily pretreated patients. 

The AFM13-NK cell combination demonstrated a compelling safety profile, with no incidences of CRS, neurotoxicity, or graft-versus-host disease. NK cells showed peak levels in circulation one day post-infusion, trafficked effectively to tumor sites, and persisted for up to three weeks. Clinical responses were notable, with an overall response rate of 92.9% and a complete response rate of 66.7%. Longitudinal follow-up revealed durable remissions, with eleven patients maintaining CR for 14 to 40 months.

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Schedule of study treatment and correlative sampling. DOI: 10.1038/s41591-025-03640-8

First-in-Human Trial for NKG2A/PD-L1 Bispecific NKCE in Solid Tumors

The versatility of NK cell engagers continues to expand with the initiation of a first-in-human phase 1 trial for XB628, a bispecific NKCE targeting NKG2A and PD-L1. Developed through a collaboration between Invenra and Exelixis, this molecule leverages dual checkpoint modulation to enhance NK cell functionality in the tumor microenvironment. 

NKG2A, an inhibitory receptor expressed on NK cells, limits cytotoxic activity when engaged. PD-L1, a well-characterized immunosuppressive ligand, is frequently upregulated in solid tumors. XB628 was engineered to block both inhibitory axes simultaneously, restoring NK cell cytotoxicity while maintaining specificity. This strategy mirrors innovations in antibody checkpoint blockade, wherein bispecific constructs target multiple immune evasion pathways.

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