Instruct: Identify the main category of Biorxiv papers based on the titles and abstracts
Query: Drug Conjugates of Antagonistic RSPO4 Mutant For Simultaneous Targeting of LGR4/5/6 for Cancer Treatment LGR4-6 (Leucine-rich repeating containing, G-protein-coupled receptors 4, 5, and 6) are three related receptors with distinct roles in organ development and stem cell survival. All three receptors are upregulated in gastrointestinal cancers to different levels, and LGR5 has been shown to be enriched in cancer stem cells. Antibody-drug conjugates (ADCs) targeting LGR5 showed robust antitumor effect in vivo but could not eradicate tumors due to plasticity of LGR5-positive cancer cells. As LGR5-negative cells often express LGR4 or LGR6 or both, we reasoned that simultaneous targeting of all three LGRs may provide a more effective approach. R-spondins (RSPOs) bind to LGR4-6 with high affinity and potentiate Wnt signaling. We identified an RSPO4 mutant (Q65R) that retains potent LGR binding but no longer potentiates Wnt signaling. The RSPO4 mutant was fused to the N-terminus of human IgG1-Fc to create a peptibody which was then conjugated with cytotoxins monomethyl auristatin or duocarmycin by site-specific conjugation. The resulting peptibody drug conjugates (PDCs) showed potent cytotoxic effects on cancer cell lines expressing any LGR in vitro and suppressed tumor growth in vivo without inducing intestinal enlargement or other adverse effects. These results suggest that RSPO-derived PDCs may provide a novel approach to the treatment of cancers with high LGR expression.
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The categories of this paper are: cancer
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The categories of this paper are: zoology
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The categories of this paper are: bioinformatics
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The categories of this paper are: biochemistry
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The categories of this paper are: cell
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The categories of this paper are: epidemiology
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The categories of this paper are: genomics
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The categories of this paper are: scientific
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The categories of this paper are: synthetic
4
The categories of this paper are: neuroscience
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The categories of this paper are: pathology
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The categories of this paper are: developmental
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The categories of this paper are: behavior
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The categories of this paper are: systems
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The categories of this paper are: microbiology
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The categories of this paper are: plant