Abstract
MCLA-158, an LGR5 × EGFR bispecific antibody, inhibits growth and metastasis of colorectal cancer.
Major Finding: MCLA-158, an LGR5 × EGFR bispecific antibody, inhibits growth and metastasis of colorectal cancer.
Concept: MCLA-158 was identified from a screen in patient-derived organoids (PDO) of both tumor and normal origins.
Impact: PDO biobanks are useful for drug discovery, with MCLA-158 identification showing preclinical antitumor activity.
Cancer stem cells (CSC) in colorectal cancer (CRC) are thought to drive the long-term potential of tumorigenesis and are characterized by high levels of LGR5, with growth and survival of most CRC cells also dependent on receptor tyrosine kinases (RTK) such as EGFR. Herpers and colleagues sought to develop a therapeutic strategy by which they targeted these critical CSCs of CRC through use of bispecific antibodies (bAb). Using a biobank of patient-derived organoids (PDO), a screen of therapeutic bAb candidates was conducted to assess their activity in comparison to organoids derived from matched healthy colon mucosa. Twenty-eight bAbs were identified that most strongly altered CRC organoid growth, with the performance of a second subsequent screen using these 28 bAbs to determine the bAb with the highest growth inhibitory activity in the greatest number of PDOs. This led to the identification of MCLA-158, which simultaneously targets EGFR and LGR5. Characterization of MCLA-158 revealed its superior growth inhibitory properties as compared to the EGFR monoclonal antibody cetuximab in both KRAS wild-type and KRAS-mutant CRC PDO models and also demonstrated its antitumor activity in patient-derived xenograft models of colon, gastric, and esophageal cancers as well as in head and neck squamous cell carcinoma. A reduction to the detrimental effects on normal colonic stem cells when compared to EGFR inhibitory antibodies was also observed. Moreover, MCLA-158 treatment reduced metastasis in murine orthotopic xenograft models and induced EGFR internalization and degradation in an LGR5-dependent manner. In summary, this work reveals that PDOs are usable to predict drug responses as well as identified MCLA-158, a bAb that targets both EGFR and LGR5, which demonstrates greater tumor-suppressive properties and less toxicities toward normal tissue than current therapies. Additionally, these results support the progression of this bAb to the ongoing clinical trial using an antibody-dependent cellular cytotoxicity–enhanced candidate of MCLA-158 in various solid tumors.
Note:Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
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