Targeting Tumors Smarter: How Organoids Accelerated the Rise of Petosemtamab (MCLA-158)

BACKGROUND

Recently, the FDA announced plans to phase out animal testing requirements for the development of monoclonal antibodies (mAbs), in favor of more human-relevant methods (1).

Among the proposed alternative approaches are:

AI-driven models to predict binding affinity and toxicity
Patient-derived organoids
Organ-on-a-chip systems

This move signals a strategic shift toward faster drug development processes while reducing the reliance on laboratory animals.

FEASIBILITY OF ORGANOIDS FOR EARLY DRUG DISCOVERY: THE PRACTICAL EXAMPLE OF MCLA-158

A great example of how patient-derived organoids can speed up early drug discovery is the development of MCLA-158 (petosemtamab) by the biotech company Merus N.V. in collaboration with research teams at IRB Barcelona.

MCLA-158 (Petosemtamab) is a bispecific antibody that targets (2):

👉🏻 EGFR (epidermal growth factor receptor): blocking of oncogenic signalling and induction of receptor degradation

👉🏻 LGR5 (leucine-rich repeat–containing G-protein–coupled receptor 5): allowing the selective delivery of the antibody to cancer stem cells (CSCS) while sparing healthy cells.

Altogether, its mechanism of action (MoA) relies on the simultaneous shut down of the oncogenic EGFR-driven proliferation of cancer cells while targeting the disease reservoir of CSCs. Moreover, MCLA-158 could block metastasis initiation in preclinical in vivo models (2).

EXPERIMENTAL DEVELOPMENT

MCLA-158 was developed through the generation of an impressive Organoid Bank using primary samples from cancer patients.

By using non cancerous tissues-derived organoids, it was possible to assess potential toxicity on healthy cells.

The use of Merus´proprietary technology, the Biclonics® platform, allowed the functional screening of the organoids, leading to the generation of a scalable Ab characterised by enhanced ADCC.

CLINICAL DEVELOPMENT

MCLA-158 is currently being evaluated in Phase 1/2/3 trials for different solid tumors (3):

– Metastatic colorectal cancer (mCRC).

– Head and Neck Squamous Cell Carcinoma (HNSCC).

– Future directions: clinical studies with MCLA-158 in gastric/esophageal cancers.

SUMMARY

MCLA-158 (petosemtamab) is the first antibody generated through organoid-based screening, demonstrating the feasibility of using patient-derived organoids in early drug discovery.
This innovative approach enabled the identification of a potent bispecific antibody with promising preclinical efficacy across multiple solid tumors, including head and neck squamous cell carcinoma (HNSCC) and colorectal cancer (CRC).
This success highlights the transformative potential of organoid-based platforms to accelerate the development of more targeted and physiologically relevant therapies in the future.