Supplementary Table S1. Total list of detection antibodies used for reverse phase protein array.

Supplementary Methods. Description of methods used for assessment of synergy, immunohistochemistry, cell death, cell cycle arrest, ADCC and CDC.

Supplementary Figure 2 from Sym004: A Novel Synergistic Anti–Epidermal Growth Factor Receptor Antibody Mixture with Superior Anticancer Efficacy

Supplementary Table S3. Limma output from comparison of 4626 with parental SNU-5 cells treated with emibetuzumab.

Suppl. Figure 1 In vivo efficacy of Sym015 treatment at various dose levels in the EBC-1 xenograft model. Suppl. Figure 2 In vivo efficacy of Sym015 and unbalanced mixtures of the two constituent antibodies Hu9006 and Hu9338, applied at 10 mg/kg or 50 mg/kg doses in the EBC-1 xenograft model. Suppl. Figure 3 In vivo efficacy of Sym015 treatment in the H596 CDX model, which harbors a MET exon 14 deletion without MET gene amplification. Suppl. Figure 4 2 Map of clinically relevant mutations, obtained from the Cancer Cell Line Encyclopedia(31), in 64 cell lines. Suppl. Table S1 List of the 64 cell lines used in the study with information on tissue of origin, supplier, and growth medium used for propagation. Suppl. Table S2 Yellow columns: FISH scores for CDX and PDX models, denoting the average number of MET and CEP7 signals per cell, the MET/CEP7 ratio, and the percentage of tumor cells amplified. Suppl. Table S3 Prediction of human pharmacokinetics based on one-species allometric scaling(33).

Supplementary Figure and Table Legends from Sym004: A Novel Synergistic Anti–Epidermal Growth Factor Receptor Antibody Mixture with Superior Anticancer Efficacy

Supplementary Tables S1-2. Table S1 - Source, origin, subtype and growth medium for each cell line. Table S2 - Characteristics of tested patient-derived xenograft models.

Supplementary Table S5. Detection of HGF in cell supernatants.

Supplementary Table S4. Sensitivity of emibetuzumab-resistant cell lines to various TKIs compared with SNU-5 cells.

Figure legend to Supplementary Figure S1.

Table S1 contains IC50 values for cetuximab inhibition, EGFR mutation and amplification status of tested cell lines. Figure S1 shows cetuximab binding to surface EGFR on HN5 and cetuximab resistant HN5 cell lines. Figure S2 shows EGFR levels in parental HN5 cells and cetuximab resistant clones. Figure S3 Overexposed image of immunoblot presented in Figure 2B. Figure S4 shows EGFR degradation upon treatment with anti-EGFR 2mixture for 48h. Figure S5 shows LNA-mediated knockdown of EGFR inhibit growth and proliferation of HN5, HN5 CR2, and HN5 CR14. Figure S6 EGFR levels in FaDu versus cetuximab resistant FaDu cell lines. Figure S7 HER3 and IGF1R plasticity as a mechanism of acquired cetuximab resistance in HN5 CR14. Figure S8 Full dose-response curves of cetuximab and EGFR+HER3+IGF1R 5 mixture in a panel of SCCUAT cell lines.

Supplementary Figure S1. Sequence homology to human and mouse reference genomes. Supplementary Figure S2. No SNU-5 tumors establish upon continuous treatment with emibetuzumab Supplementary Figure S3. MET level in 7333 and with or without emibetuzumab treatment. Supplementary Figure S4. Log2 ratios for MYC, PVT1, and ERBB3 copy number gains in the 4626 tumor. Supplementary Figure S5. HER3 level in SNU-5 cell lines. Supplementary Figure S6. Both emibetuzumab-resistant cell lines are resistant to Sym015 in vitro. Supplementary Figure S7. SNU-5 are equally sensitive to Sym015 and Sym015 LALA in vivo.

Supplementary Table S2. Limma output from comparison of 7333 with parental SNU-5 cells treated with emibetuzumab.

Supplementary Figures S1-8. Figure S1 - Analysis of nonlinear blending synergy for the pairs of antibodies that constitute Pan-HER. Figure S2 - In vitro comparison of Pan-HER and a combination of cetuximab, trastuzumab and MM-121. Figure S3 - In vivo assessment of nonlinear blending synergy for the target specificities in the Pan-HER mixture. Figure S4 - Dose titration of Pan-HER in the BxPC3 xenograft model. Figure S5 - IHC analysis of Calu-3 tumors. Figure S6 - Assessment of cell death and cell cycle arrest. Figure S7 - Assessment of ADCC in a panel of cell lines. Figure S8 - Analysis of the effect of receptor internalization on effector functions.

Additional effect of Pan-HER radiation on DNA damage repair

Supplementary Materials and Methods and Figure Legends

Supplementary Figures and Material and Methods

Supplementary figure 1. Sym015 inhibits viability of cell lines in a synergic manner; Supplementary figure 2. The Sym015 antibodies Hu9338 and Hu9006 bind to 2nd or 3rd blades of MET and block HGF binding; Supplementary figure 3. Sym015 induces MET internalization and degradation in MKN-45 cells; Supplementary figure 4. Sym015 induces MET internalization and degradation in EBC-1 cells; Supplementary figure 5. Sym015 induces MET degradation in MKN-45 and EBC-1 cells; Supplementary figure 6. Sym015 inhibits signaling by MET in EBC-1 cells; Supplementary figure 7. Sym015 inhibits motility of EBC-1

Figure S1: EGFR mutants binding to CTX, Sym004, PNM Figure S2: Clonogenic assay in EGFR mutants with CTX, Sym004, PNM