Table 2.
Comparison of murine, chimeric, and humanized mAbs. Current clinical trials of anti-GD2 mAbs.
| Murine | Chimeric | Humanized | ||||
|---|---|---|---|---|---|---|
| Structure | 3F8 and 14.18 from murine IgG3 14G2a: IgG2a-class switch variant from 14.18 ME36.1: IgG2a- and IgG1-switch variant from murine IgG3 |
ch14.18: fusing heavy and light chains of 14.18 Dinutuximab generated by SP2.0 cells Dinutuximab β generated by CHO cells |
hu14.18K322A: single amino acid substitution in the Fc region of K322A (humanized dinutuximab) generated by YB2.0 cells hu3F8: fusion of complementarity-determining regions with the human IgG1 framework (naxitamab) |
|||
| Binding affinity to the GD2 target | 3F8 has higher affinity than ME36.1 and 14.G2a | ch14.18 and 14.G2a exhibit equal affinity | hu3F8 has a 10-fold higher affinity than ch14.18 | |||
| m3F8 > hu3F8 > ch14.18 | ||||||
| ADCC CDC |
14.G2a has higher ADCC than 14.18 3F8 has higher CDC than ch14.18 |
ch14.18 and 14.G2a are equally capable of mediation of CDC ch14.18 has a 50-100 fold higher ADCC than 14.G2a Dinutuximab β has higher ADCC than dinutuximab |
mAbs generated by YB2/0 cells have higher ADCC than mAbs generated by CHO cells K322A mutation led to decreased CDC hu3F8 has higher ADCC (not CDC) than ch14.18 |
|||
| hu3F8 > ch14.18 > m3F8 m3F8 > ch14.18 > hu3F8 | ||||||
| Features and therapy | ME36.1: cross reaction with GD2 and GD3 3F8 and 14.G2a widely used as monotherapy |
Less immunogenic than murine mAbs ch14.18 has a longer half-life than hu3F8 2 drugs officially approved Long-term results comparable to oral chemotherapy |
Less immunogenic than chimeric mAbs hu14.18K322A was developed to reduce neuropathic toxicity and pain hu3F8 has significant antitumor efficacy Naxitamab officially approved |
|||
| Limitations and adverse effects | HAMA Most common adverse effects include allodynia, pain, hypertension, hypotension, apnea, tachycardia, fever, allergic reaction Treatment with 14G2a caused severe pain, with 3F8 caused reversible encephalopathy syndrome Less common adverse effects include hyponatremia/kalemia, nausea, vomiting, diarrhea, liver dysfunction, hypoxia |
HACA Adverse effects comparable to murine mAbs Dinutuximab/beta treatment resulted in demyelinating polyneuropathy, and ocular signs present with ophthalmoplegia, mydriasis, and accommodation deficit Continuous infusion can only reduce pain intensity |
HAHA hu14.18K322A has a higher HAHA response rate compared to hu3F8 Moderate adverse effects Treatment can be carried out on an outpatient basis |
|||
| Treatment mAbs with IL-2 associated with capillary leak syndrome | ||||||
| GD2-targeting therapy: current clinical trials with mAbs | ||||||
| hu3F8 | (active, not recruiting) NCT02650648 NCT01757626 (recruiting) NCT05489887 NCT06026657 NCT02502786 NCT03363373 |
hu3F8 plus NK cells, cyclophosphamide hu3F8 plus GM-CSF hu3F8 with/without ceritinib TGFβi NK cells plus gemcitabine with/without hu3F8 hu3F8 plus GM-CSF hu3F8 plus GM-CSF |
Neuroblastoma Neuroblastoma Neuroblastoma Breast Cancers Osteosarcoma Neuroblastoma |
Phase I Phase I/II Phase II Phase Ib/II Phase II Phase II |
||
| hu14.18K322A | NCT01857934 (active, not recruiting) | hu14.18K322A with induction chemotherapy | Neuroblastoma | Phase II | ||
| ch14.18/SP2.0 | (active, not recruiting) NCT03786783 NCT01711554 (recruiting) NCT05400603 NCT03794349 NCT05421897 |
ch14.18/SP2.0 plus GM-CSF with chemotherapy ch14.18/SP2.0 plus lenalidomide with/without isotretinoin γδ T cells with ch14.18/SP2.0, temozolomide, irinotecan and zoledronate ch14.18/SP2.0, irinotecan and temozolomide and with/without eflornithine ch14.18/SP2.0 with chemotherapy |
Neuroblastoma Neuroblastoma Neuroblastoma Neuroblastoma Neuroblastoma |
Phase II Phase I Phase I Phase II Phase IV |
||
| ch14.18/CHO | (active, not recruiting) NCT02743429 (recruiting) NCT02914405 NCT05272371 NCT06071897 NCT05080790 NCT05754684 NCT01704716 |
ch14.18/CHO continuous infusion 131-1 mIBG followed by nivolumab and ch14.18/CHO ch14.18/CHO with chemotherapy ch14.18/CHO with induction chemotherapy ch14.18/CHO with zoledronic acid and IL-2 ch14.18/CHO plus NK cells, IL-2, GM-CSF and spironolactone ch14.18/CHO with induction chemotherapy plus isotretinoin with/without IL-2 |
Neuroblastoma Neuroblastoma Neuroblastoma Neuroblastoma and Ganglioneuroblastoma Leiomyosarcoma Neuroblastoma Neuroblastoma |
Phase II Phase I Phase I Phase III Phase II Phase II Phase III |
||
Antibody-dependent cell-mediated cytotoxicity/antibody-dependent cellular phagocytosis (ADCC/ADCP), complement-dependent cytotoxicity (CDC), human anti-murine/-chimeric/-human antibodies (HAMA, HACA, and HAHA), chinese hamster ovary (CHO), granulocyte-macrophage colony-stimulating factor (GM-CSF), transforming growth factor β imprinted (TGFβi) NK cells, metaiodbenzylguanidine (mIBG).