This PDF file includes:

• Fig. S1. Procedures of stepwise engineering to generate the second-generation active RAS-specific iMab, inRas37.
• Fig. S2. Preparation of the RT22 VH and in4 cyclic peptide and biochemical characterization of inRas37.
• Fig. S3. inRas37 has more potent antitumor efficacy in vivo than RT11-i does, without noticeable toxic side effects.
• Fig. S4. inRas37 causes dose-dependent inhibition of in vivo growth of KRAS^G12V SW480 tumor xenografts in mice.
• Fig. S5. Comparison of cell surface expression levels of integrin ανβ5 and integrin ανβ3 in various RAS^WT and RAS^MUT cell lines.
• Fig. S6. inRas37 suppresses the in vivo growth of various RAS^MUT tumor xenografts in mice without noticeable systemic toxicity.
• Fig. S7. IHC and Western blot analyses of tumor tissues excised from mice after treatment.
• Fig. S8. Combined treatment of KRAS^MUT cell lines with a pharmacological inhibitor and either inRas37 or inCT37.
• Table S1. Binding constants for the interactions of inRas37 with GppNHp-loaded active forms of RAS, as determined by SPR analysis.
• Table S2. Binding constants for the interactions of inRas37 with integrin ανβ5 and integrin ανβ3, as determined at pH 7.4 and/or pH 6.0 by biolayer interferometry.
• Table S3. Quantitative assessment of the cellular uptake and cytosolic concentrations of RT11-i and inRas37 in HeLa and SW480 cells.
• Table S4. CRC driver mutations from the CCLE and COSMIC datasets.
• Table S5. List of resources (antibodies, recombinant proteins, and chemicals) used in this study.

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