NK Cell Engager Development Faces Mounting Setbacks as BeOne Medicines and Novartis Discontinue Programs
核心洞察
BeOne Medicines (搜索) has halted development of its anti-MUC1 (搜索) NK-cell engager MAb BGB-B3277 (搜索) due to a sponsor decision, marking another setback for the NK-cell engager field.
Novartis terminated its NKG2D-targeting fusion protein QEQ278 after three years of development, citing business decision following lack of activity with no responses among 30 patients and severe adverse events in half of participants.
The NK-cell engager field continues to be characterized more by program discontinuations than successful arrivals, despite initial promise as an extension of immune-oncology approaches.
The NK-cell engager field has suffered another significant blow as BeOne Medicines (搜索) discontinued its anti-MUC1 (搜索) NK-cell engager MAb BGB-B3277 (搜索), adding to a growing list of terminated programs that highlight the challenges facing this immune-oncology approach.
According to an update posted on clinicaltrials.gov, BeOne Medicines (搜索) halted the first-in-human trial of BGB-B3277 (搜索) due to a "sponsor decision." The CD16A (搜索)-engaging bispecific was specifically designed to target the membrane-proximal epitope of MUC1 (搜索) in an effort to avoid the sink effect by minimizing binding to soluble MUC1. However, like many other programs in this space, the effort stalled before generating meaningful clinical data.
Novartis Abandons NKG2D Approach
The discontinuation follows Novartis's recent decision to terminate QEQ278, a fusion protein targeting NKG2D, after three years of clinical development. The study was marked as terminated on clinicaltrials.gov with "business decision" cited as the reason, likely relating to the molecule's lack of clinical activity.
The first results from QEQ278's late-line solid tumor (搜索) trial, presented at last October's Triple (AACR-NCI-EORTC) meeting, showed no responses among 30 patients. Notably, half of the patients experienced severe adverse events, and there were two dose-limiting adverse events noted. The therapeutic logic behind QEQ278 was to drive tumor cell killing by targeting cells expressing the NKG2D ligand while neutralizing soluble NKG2D-L to resensitize NK cells.
Pattern of Attrition in NK-Cell Engagers
The field of NK-cell engagers, once positioned as a promising extension of the immune-oncology playbook, has been characterized more by attrition than successful arrivals. AbbVie (搜索) quietly terminated the Dragonfly-derived anti-NKG2D x cMet bispecific NK-cell engager ABBV-303 last year, adding to the conspicuous trail of discontinued programs.
Despite these setbacks, NKG2D and NKG2D-L remain popular targets for cell therapy development, particularly Car-NK projects. However, the pipeline of protein and monoclonal antibody therapeutics with this mechanism remains sparse, including CD16A (搜索)-targeting NK-cell engagers that have faced their own challenges.
MUC1 Targeting Continues Despite Challenges
MUC1 (搜索) itself has long been a frustrating target for drug developers. Despite mixed and often negative clinical results over the years, companies continue to pursue tumor-associated MUC1, believing that improved antibody design or more potent payloads might finally unlock its therapeutic potential.
Daiichi Sankyo is developing a TA-MUC1 (搜索)-targeting ADC, sacomitatug deruxtecan (搜索), which recently emerged to use an analogue of the antibody gatipotuzumab, acquired for $133 million from Glycotope last year. Meanwhile, Merck KGaA is pursuing a different bispecific approach, focusing on dendritic cells and macrophage activation with M0324 (搜索), an anti-MUC1 x CD40 (搜索) project that recently entered the clinic.
This marks Merck KGaA's second bispecific targeting MUC1 (搜索) to enter clinical testing. The company's previous candidate, an anti-EGFR (搜索) x MUC1 ADC called M1231, was discontinued due to "strategic considerations." However, the company has not completely abandoned this approach, developing another anti-EGFR x MUC1 ADC in 2024 using exatecan as a payload rather than the hiasterlin warhead deployed in M1231.
Other groups, including SPARC and Minerva Biotechnologies, also retain programs against MUC1 (搜索), indicating that despite repeated setbacks, both MUC1 and NK-cell engagers remain active areas of development. However, clinical validation for these approaches continues to prove elusive, raising questions about the viability of these therapeutic modalities in their current forms.