Targeting cancer stem cell antigens: novel dual antibodies have great potential

On April 26, 2022, the journal Nature Cancer published a research article on EGFR/LGR5 double antibody by Merus and scientists from the Barcelona Institute of Science and Technology, Spain
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The researchers focused their thinking on cancer treatment on cancer stem cell antigens, including LGR5, ZNFR3, RNF43, etc.
These targets have not been the direction of antibody drug development before
.

The researchers generated 54 Fabs against the cancer stem cell antigens LGR4, LGR5, ZNFR3, and RNF43, combined with 4 EGFR antibodies and 4 HER3 antibodies, and obtained more than 500 double-antibody combinations
.

Then, it was screened on a human tumor organoid model, and the EGFR/LGR5 double antibody MCLA-158 was obtained.
MCLA-158 was constructed using Merus' Biclonics double antibody technology platform, and the affinities for EGFR and LGR5 were 0.
22nM and 0.
86nM, respectively
.

The antitumor activity of MCLA-158 significantly exceeds that of EGFR mAb
.

MCLA-158 can efficiently mediate the endocytosis and degradation of EGFR, but EGFR mAb has no such effect
.

In October last year, Merus disclosed the preliminary clinical data of the first phase of MCLA-158, which enrolled 10 patients, who had received second-line treatment on average, 10 patients had received chemotherapy, and 9 patients had received PD-(L)1 Antibody therapy
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In 7 evaluable patients, all tumors shrank, the disease control rate was 100%, and the ORR was 43% (3/7)
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In conclusion, the research and development idea of ​​MCLA-158 is extremely novel, focusing on the antigen targets of cancer stem cells, constructing double antibodies with EGFR and HER3, and screening candidate double antibody molecules through tumor organoids
.

Compared with EGFR monoclonal antibody, the screened EGFR/LGR5 double antibody has a different mechanism of action, and also shows better efficacy and better safety
.

Cancer stem cell antigen targets can obviously also be combined with more TAAs to build more iterative double-antibody drugs
.

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