TABLE 2.
Clinical studies of anti-TNFRSF agonistic antibodies for cancer treatment, alone or in combination.
| Target | Agent | Molecule | Clinical Status | Key Findings | NCT number |
|---|---|---|---|---|---|
| TNFRSF4 (OX40) | Ivuxolimab (PF-04518600) | IgG2 | II (FIH 2015) | • No DLTs (0.01 to 10 mg/kg) | NCT02315066 |
| • Monotherapy: ORR 4% Diab et al. (2016); Diab et al. (2022) | |||||
| Tavolimab (MEDI-0562) | IgG1 | I (FIH 2015) | • No DLTs (0.03 to 10 mg/kg) | NCT02318394 | |
| • Monotherapy: 2 immune-related PR Glisson et al. (2020) | |||||
| MEDI6469 | IgG1 | I/II (FIH 2003) | • No MTD reached (0.1 to 2 mg/kg) | NCT02559024 | |
| • Monotherapy: ORR 0% Curti et al. (2013) | |||||
| GSK3174998 | IgG1 | I/II (FIH 2015) | • No MTD established (0.003 to 10 mg/kg) | NCT02528357 | |
| • Monotherapy: ORR 2.2% | |||||
| • GSK3174998/pembrolizumab; ORR 8% Postel-Vinay et al. (2020) | |||||
| Vonlerolizumab (MOXR0916) | IgG1 | I (FIH 2015) | • No DLTs (0.2–1200 mg) Hansen et al. (2016) | NCT02219724 NCT02410512 | |
| • Vonlerolizumab/atezolizumab; ORR 4% Infante et al. (2016) | |||||
| TNFRSF5 (CD40) | Selicrelumab (CP-870893, RG-7876) | IgG2 | I (FIH 2004) | • Strong agonistic activity | NCT02225002 NCT01103635 NCT02157831 NCT00607048 NCT01456585 NCT00711191 |
| • MTD 0.2 mg/kg, ORR 14% Vonderheide et al. (2007) | |||||
| • Monotherapy (weekly dosing) for solid tumor: ORR 0% Rüter et al. (2010) | |||||
| • CP-870893/chemo for solid tumors: ORR 20%–40% Beatty et al. (2013), Vonderheide et al. (2013), Nowak et al. (2015) | |||||
| Sotigalimab (APX005M) | IgG1 mutant (S267E) | I/II (FIH 2015) | • Strong FcγRIIB binding | NCT03123783 NCT02482168 NCT03502330 | |
| • RP2D: 0.3 mg/kg, Johnson et al. (2017) | |||||
| • APX005M/chemo w/w.o. Nivo for pancreatic cancer: ORR 58% O'Hara et al. (2019) | |||||
| ChiLob7/4 | IgG1 | I (FIH 2007) | • MTD 200 mg | NCT01561911 | |
| • Monotherapy: ORR 0% Johnson et al. (2015) | |||||
| SEA-CD40 | IgG1 nonfucosylated | I (FIH 2015) | • Enhanced SEA-CD40/FcγRIIIa binding Gardai et al. (2016) | NCT02376699 NCT04993677 | |
| • 5 DLTs (0.6–60 mcg/kg or 30 mcg/kg) | |||||
| • 1 PR,10 SD, DCR 32% Grilley-Olson et al. (2018) | |||||
| CDX-1140 | IgG2 | I/II (FIH 2017) | • RP2D 1.5 mg/kg Sanborn et al. (2020) | NCT03329950 | |
| LVGN7409 | IgG mutant | I (FIH 2020) | • TBD Fu et al. (2022) | NCT04635995 NCT05152212 NCT05075993 | |
| Mitazalimab (ADC1013 | IgG1 | I/II (FIH 2015) | • RP2D 0.9–1.2 mg/kg Deronic et al. (2021), Enell Smith et al. (2021) | NCT02379741 NCT02829099 NCT04888312 | |
| YH003 | IgG2 | I/II (FIH 2021) | • No DLTs (0.03–0.3 mg/kg) | NCT04481009 | |
| • YH003/Toripalimab: 1PR Coward et al. (2021) | |||||
| GEN 1042 | Bispecific (CD40xCD137) | I/II (FIH 2019) | • No MTD reached (0.1–400 mg) Johnson et al. (2021) | NCT04083599 | |
| RO7122290 | Bispecific (FAPxCD40) | I (FIH 2017) | • No MTD reached (5 — 2000 mg) Melero et al. (2020) | NCT03869190 | |
| TNFRSF7 (CD27) | Varlilumab (CDX-1127) | IgG1 | I/II (FIH 2011) | • No DLT (0.1–10 mg/kg) | NCT01460134 |
| • Monotherapy: 0%-10% Ansell et al. (2020) | |||||
| TNFRSF9 (CD137) | Urelumab (BMS-663513) | IgG4 | I/II (FIH 2005) | • Strong agonistic activity | NCT01471210 NCT01775631 NCT02110082 NCT00461110 NCT00351325 NCT00309023 NCT02534506 NCT02253992 |
| • RP2D 0.1-0.3 mg/kg Segal et al. (2017) | |||||
| • Monotherapy for R/R NHL: 6%–35% | |||||
| • Urelumab/rituximab: ORR 10%–30% Timmerman et al. (2020) | |||||
| • Urelumab/nivolumab: ORR 4.5%–50% Massarelli et al. (2016) | |||||
| Utomilumab (PF-05082566) | IgG2 | I/II (FIH 2011) | • Weak agonistic activity | NCT02179918 NCT02444793 NCT01307267 | |
| • No DLT (0.006-10 mg/kg) Segal et al. (2018) | |||||
| • Monotherapy; ORR 3.8% Segal et al. (2018) | |||||
| • Utomilumab/rituximab for R/R NHL; ORR 21.2% Gopal et al. (2020) | |||||
| • Utomilumab/pembrolizumab; ORR 26.1% Tolcher et al. (2017) | |||||
| LVGN6051 | IgG mutant | I/II (FIH 2019) | • RP2D: 4 mg/kg Qi et al. (2019), Fu et al. (2021) | NCT04130542 NCT04694781 NCT05075993 | |
| ADG106 | IgG4 | I/II (FIH 2018) | • RP2D: 5 mg/kg Zhang et al. (2020) | NCT03802955 NCT03707093 | |
| CTX-471 | IgG4 | I (FIH 2019) | • RP2D: 0.3, 0.6 mg/kg | NCT03881488 | |
| • Monotherapy: 3PR, ORR 8% Compass Therapeutics (2022) | |||||
| Cinrebafusp alfa (PRS-343) | Bispecific antibody (HER2 x CD137) | I (FIH 2017) | • Monotherapy: 1CR, 3PR | NCT03330561 NCT03650348 | |
| • Cinrebafusp alfa / atezolizumab: 4PR Ku et al. (2020) | |||||
| GEN1046 | Bispecific antibody (PD-L1 xCD137) | I/II (FIH 2019) | • DCR 65.6% Muik et al. (2022) | NCT03917381 | |
| TNFRSF18 (GITR) | TRX-518 | IgG1 | I/II (FIH 2010) | • No DLT (0.0001 to 8 mg/kg) | NCT01239134 NCT02628574 |
| • Monotherapy: ORR 0% Koon et al. (2016) | |||||
| MK-4166 | IgG1 | I (FIH 2014) | • No MTD reached (0.0015-900 mg) | NCT02132754 | |
| • Monotherapy: ORR 0% Papadopoulos et al. (2019) | |||||
| MK-1248 | IgG4 | I/II (FIH 2015) | • No DLT up to 170 mg | NCT02553499 | |
| • Monotherapy; ORR 0% | |||||
| • MK-1248/pembrolizumab; ORR 18% Geva et al. (2020) | |||||
| BMS-986156 | IgG1 | I/II (FIH 2015) | • No DLT (10–800 mg) | NCT02598960 NCT04021043 | |
| • Monotherapy: ORR 0% | |||||
| • BMS-986156/nivolumab: ORR 2.7%–14.3% Heinhuis et al. (2020) | |||||
| Efgivanermin alfa (MEDI 1873) | IgG1 | I (FIH 2015) | • No MTD reached up to 750 mg | NCT02583165 | |
| • Monotherapy; ORR 0% Balmanoukian et al. (2020) |