Table 2.
Selected therapeutic antibodies with low or no fucose, approved by FDA/EU or in clinical development.
| Antibody name (code) | Antigen | Antibody isotype | Method of defucosylation | % fucose | Diseases | Major findings | references |
|---|---|---|---|---|---|---|---|
| 1.1. Approved antibodies (FDA/EU) | |||||||
| Obinutuzumab (GA101) | CD20 | Humanized IgG1 | CHO overexpressing GnTIII (GlycoMAb) | About 15% | B-NHL | Higher ADCC by NK and ɣδ Tells, more effective than RTX in vivo in some mice models or in primates | (47, 55, 58–62) (63) |
| Phase III in CLL compared to RTX in combination with CLb | (64) | ||||||
| Phase III studies with different chemotherapy regimen in CLL and compared to RTX | (65) | ||||||
| Phase III studies in diff chemo combinations compared to RTX in untreated FL. | (66) | ||||||
| Mogamulizumab (KW-7061) |
CCR4 | Humanized IgG1 | CHO FUT8 -/- (Potelligent) | 0% | Cutaneous T cell lymphoma | Equivalent ADCC by afucosylated mAb, but with 10-fold lower antigen expression on target compared to fucosylated mAb | (67, 68) |
| Inebilizumab (MEDI 551) |
CD19 | Humanized IgG1 | CHO FUT8 -/-
(Potelligent) |
0% | Neuromyelitis optica | Increased ADCC in vitro. Depletes B cells more effectively than fucosylated antibody in hCD19 transgenic mice (PB, spleen and BM) | (69–72) |
| Benralizumab (MEDI-563) | IL-5Rα | Humanized IgG1 | CHO FUT8 -/-
(Potelligent) |
0% | Severe asthma with eosinophilia | Increased ADCC in vitro. Efficacy in depleting eosinophil in non-human primates and in clinical Phase III studies | (73–75) |
| Margetuximab (MGAH22) |
HER2 | Chimeric IgG1 | CHO FUT8 -/-
Also mutation in Fc to decreased CD32B binding |
0% | Advanced metastatic HER2+++ breast cancer | Increased ADCC. In vivo increased activity in hFcɣRIII+ mice. Phase III trial in breast cancer compared to trastuzumab |
(76, 77) |
| Belantamab vedotin (GSK2857916) |
BCMA | IgG1-MMAF ADC | CHO FUT8 -/- | 0% | Multiple myeloma | Increased ADCC of naked mAbs. Phase II ORR 31%. 72% survival at 6 months | (78) |
| Amivantamab (JNJ-61186372) |
EGFRxMET | Humanized bispecificIgG1 | Low fucose producing cell line | <10% | Non-small cell lung cancer (NSCLC) | Increased ADCC, not ADCP compared to high fucose variant. Phase III NSCLC | (79) |
| 1.2. Selected antibodies in clinical studies | |||||||
| Ublituximab (Emab-6) | CD20 | Chimeric IgG1 | YB2/0 | 24% | CLL, B-NHL, multiple sclerosis, neuromyelitis optica | High ADCC and ADCP (not compared with fully fucosylated antibodies). Phase I and II trials in B-NHL, CLL and autoimmune diseases + neuromyelitis optica. Phase III in CLL with or w/o ibrutinib (ORR 85% vs 65%) | (80–82) |
| Tomuzotuximab (cetuGEX) | EGFR | Humanized IgG1 (cetuximab seq) | Glyco Express System® | 0% | Advanced carcinoma | Increased ADCC in vitro, Phase I study | |
| Phase II study comparing CetuGEX with cetuximab combined with chemo: no difference observed | (83) | ||||||
| Imgatuzumab GA201 (RG7160) | EGFR | Humanized rat IgG1 (ICR62) | CHO stably expressing GnTIII (GlycomAb) | 15% | Carcinoma | Increased ADCC in vitro. Higher efficacy in mouse models (SCID beige or SCID hFcɣRIIIA tg) also in combination with chemotherapy | (84) |
| Phase I study in EGF+++ solid tumors | (85) | ||||||
| Open label study in advanced CRC. Decrease NK post treatment in PB | (86) | ||||||
| Enhanced ADCC in vitro | (87) | ||||||
| Favorable combination of GA201 and chemo in vitro and in carcinoma models in SCID mice | (88) | ||||||
| Open label study of GA201 vs cetuximab in head & neck squamous carcinoma (N=44). Greater decrease in NK in PB and greater cytokine release with GA201 vs CTX. No difference in clinical response. | (89) | ||||||
| KHK4083 | OX40 | Human IgG1 | FUT8 -/-Potelligent | 0% | Ulcerative colitis | Phase I | (90) |
| Tragex | HER2 | Humanized IgG1 | Glyco Express system®
(FUT8-/-) |
HER2+++ tumors | Increased ADCC in vitro. Enhanced activity in vivo in hFcɣRIIIA tg mice. Phase I in HER2+++ solid tumors |
(37, 91–94) | |
| Cusatuzumab (JNJ-74494550, ARGX-110) | CD70 | Humanized IgG1 | CHO FUT8 ko (Potelligent) | 0% | Hematological and solid cancers | Phase I study | (95, 96) |
| Bemarituzumab (AMG 522) | FGFR2b | Humanized IgG1 | CHO FUT8 | 0% | Gastric cancer FGFR2b+++ | Increased ADCC in vitro. Efficacy in vivo in mouse sc SCID model. Recruitment of NK and T cells into tumor. | (97, 98) |
ADCC, Antibody dependent cellular cytotoxicity; ADCP, Antibody dependent cellular phagocytosis; BM, Bone marrow; B-NHL, B-Non Hodgkin’s lymphoma; CLb, chlorambucil; CLL, Chronic lymphocytic leukemia; CR, Complete response; EGFR, Epidermal growth factor receptor; FL, follicular lymphoma; PB, Peripheral blood; NSCLC, Non-small cell lung cancer; ORR, Overall response rate; RTX, Rituximab; SCID, Severe combined immunodeficient.