DC101

The anti-vascular endothelial growth factor receptor 2 (VEGFR2) antibody ramucirumab has shown promise in unresectable HCC with high serum alpha-fetoprotein (AFP) levels, but its efficacy after Atezolizumab/Bevacizumab is unclear. Furthermore, single-cell analysis demonstrated that DC101 suppresses CSCs by disrupting their interaction with ECs and induces alterations in the tumor immune microenvironment. VEGFR2-targeted therapy not only suppressed tumor angiogenesis but also inhibited CSCs and enhanced antitumor immune activity, suggesting its potential utility as a second-line treatment following Atezolizumab/Bevacizumab.

Obeying these principles, we find DC101 radiosensitizes SSR, DNA double strand break unrepair and tumor cure by 4-8Gy at all clinically-relevant doses. Critically, DC101 fails to sensitize small intestinal endothelial injury or lethality from the gastrointestinal-acute radiation syndrome.

These findings suggest that the mechanical barrier of HA is the major reason responsible for the resistance developed during prolonged anti-angiogenesis in EGC. Incorporating PEGPH20 into the existing treatment regimen is promising to improve outcomes for patients with EGC.

In this study, we showed that cabozantinib activated the innate immune system, and lenvatinib and AZD4547, which commonly inhibit FGFR signaling, altered TIME to a hot immune state by downregulating lipid metabolism-related genes. These findings support the therapeutic use of combination immunotherapies.

Ramucirumab, an anti-VEGFR2 antibody, has been shown to be effective for advanced HCC with high AFP levels, but its efficacy after ABC therapy is unclear. The anti-VEGFR2 antibody not only inhibits angiogenesis but also suppresses cancer stem cells and activates tumor immunity, and it might be effective in AFP-positive advanced HCC after ABC therapy.

When combined with an ICI and paclitaxel, only DC101 pre-administration significantly inhibited tumor growth, but simultaneous administration did not. AI pre-administration, and not simultaneous administration, may increase the therapeutic effects of ICIs due to improved immune cell infiltration.

Moreover, DC101 enhanced the infiltration of dendritic cells and B cells, and local HEV formation. In conclusion, our data indicate that DC101 may be a better choice for the combined clinical application of ICIs and anti-angiogenic agents.

VEGF blockade using specific antibodies against VEGF or VEGFR2 increased HEVs in the TME and cytotoxic CD8(+) TILs, significantly improving the therapeutic efficacy of EAT strategies in preclinical models, supporting the clinical investigation of VEGF blockades to further enhance BsAb-based T cell immunotherapies.

Furthermore, HC-7366 showed significant benefit in colorectal models when combined with DC101 (anti-VEGFR2 antibody), 5-fluorouracil (chemotherapy), alpelisib (PI3Kα inhibitor), or trametinib (MEK1/2 inhibitor). ATF4 and JUN transcriptional activity was enhanced with HC-7366 treatment consistent with activation of ISR. Collectively, our in vitro and in vivo results demonstrate that HC-7366 is a potent GCN2 activator with strong antitumor activity across multiple solid tumor models as a monotherapy or in combination with standard of care agents.

Finally, we injected KL murine tumor cells into immunocompetent mice, and randomly treated them with vehicle or the VEGF blocking antibody, DC101...Collectively, our data indicates that in LKB1-deficient tumors, upregulation of MYC promotes tumor cell metabolic reprogramming and that targeting MYC or MCT4 can inhibit lactate reutilization and enhance the efficacy of anti-angiogenic agents. These findings provide insight into the mechanisms driving the aggressive phenotype of KRAS-mutant LKB1-deficient tumors and identify a novel therapeutic strategy for targeting this patient population.

We have established an immune syngeneic orthotopic HCC mouse model inoculating Hep-55.1C cells into the left liver lateral lobe of C57BL/6 mice (n=5-6/group) and treated with the MTAs (lenvatinib (LEN), sorafenib (SORA), regorafenib, cabozantinib, DC101/an anti-mouse VEGFR-2 antibody)) for 2 weeks... In the orthotopic xenograft mice model for HCC, LEN and AZD4547, which commonly inhibit FGFR signaling, altered the TIME from cold to hot. The findings obtained from this study support the therapeutic concept in the era of multi-MTAs including ICIs.

DZB is also in a phase-2 trial for gastric cancer (GC), where it is combined with the current standard-of-care (SoC) paclitaxel and the VEGFR2-antibody (Ab), ramucirumab...When the mean tumor size was at least 80 mm3, mice were treated with vehicles (po, ip and iv), DZB alone (35 or 75 mg/kg, po, qd), paclitaxel (15 mg/kg, iv, qw) or the VEGFR2-Ab, DC101 (10 mg/kg, ip, 2qw)... DZB is well-tolerated when combined with paclitaxel and a VEGFR2-Ab in murine syngeneic models, and shows an additive effect in the orthotopic breast models. These data support the ongoing clinical trial with DZB in GC (FIDES-03, NCT04604132). No