Antibody–Drug Conjugates: A Review of Approved Drugs and Their Clinical Level of Evidence
Abstract
:Simple Summary
Abstract
1. Introduction
2. Antibody–Drug Conjugates
2.1. Mechanism of Action
2.2. Key Components
2.3. Target Antigen
2.4. Antibody
ADC | Targeted Tumor Antigen and Expressed Tissue | Linker | Drug Antibody Ratio | Cytotoxic Payload | Adverse Events/Toxicities | Toxicity Mechanism |
---|---|---|---|---|---|---|
1. Gemtuzumab ozogamicin (Mylotarg) | CD33 (Expressed in myeloid stem cells, myeloblasts, monoblasts, granulocyte precursors, mast cells) | Cleavable acid-labile hydrazone (chemical) | 2–3 | Calicheamicin (cytotoxic antibiotic) | Infection Hemorrhage Increased transaminases Veno-occlusive disease Thrombocytopenia | Normal tissue expression of antigen: veno-occlusive disease, hemorrhage and hepatotoxity Payload-related: hepatic dysfunction Myelosuppression |
2. Brentuximab vedotin (Adcetris) | CD30 (Expressed in a small subset of activated T and B lymphocytes, classical HL, anaplastic large cell lymphoma (ALCL), peripheral T-cell lymphoma (PTCL), adult T-cell leukemia/lymphoma; cutaneous T-cell lymphoma (CTCL); extra-nodal NK-T-cell lymphoma; and a variety of B-cell non-HLs, including diffuse large B-cell lymphoma, particularly EBV-positive diffuse large B-cell lymphoma) | Cleavable (enzymatic) | 4 | Monomethyl auristatin E (microtubule-targeting) | Peripheral sensory neuropathy Febrile neutropenia Thrombocytopenia Anemia Upper respiratory tract infection Mucositis | Payload-related: Peripheral sensory neuropathy Myelosuppression |
3. Ado- Trastuzumab emtansine (Kadcyla) | Her-2 (Expressed in breast, colon, gastric, endometrial cancer cells) | Non-cleavable (thioether) | 3–4 | DM1, derivative of maytansine (microtubule-targeting) | Thrombocytopenia Neutropenia Hypertension Increased transaminases Pneumonitis Peripheral sensory neuropathy Ocular toxicity | Normal tissue expression of antigen: Cardiac toxicity (Decrease LVEF) Payload-related: Myelosuppression Increased transaminases Peripheral sensory neuropathy Off target toxicity: Interstitial pneumonitis |
4. Inotuzumab ozogamicin (Besponsa) | CD22 (Expressed early during the ontogeny of B cells, and in the blasts of B cell acute lymphoblastic leukemia) | Cleavable acid-labile hydrazone linker (chemical) | 5–7 | Calicheamicin (cytotoxic antibiotic) | Thrombocytopenia Neutropenia Anemia Leukopenia Hemorrhage Pyrexia Headache Transaminases increased Gamma-glutamyltransferase increase Hyperbilirubinemia | Payload-related: Hepatic dysfunction Myelosuppression |
5. Polatuzumab vedotin (Polivy) | CD79b (Expressed on over 90% of B-cell NHL malignancies) | Cleavable (Enzymatic) | 3.5 | Monomethyl auristatin E (microtubule-targeting) | Neutropenia Anemia Thrombocytopenia Peripheral neuropathy | Payload-related: Peripheral sensory neuropathy Myelosuppression |
6. Enfortumab vedotin—(Padcev) | Nectin-4 (Over-expressed in several human cancers, including lung, gastric, ovarian and breast cancers) | Cleavable (Enzymatic) | 3.8 | Monomethyl auristatin E (microtubule-targeting) | Peripheral Neuropathy Decreased appetite Rash Alopecia Dysgeusia Dry Eye Dry Skin Pruritis | Normal tissue expression of antigen: Dysgeusia Payload-related: Peripheral sensory neuropathy |
7. Fam-Trastuzumab deruxtecan (Enhertu) | Her-2 (Expressed in breast, colon, gastric, endometrial cancer cells) | Cleavable (Enzymatic) | 7–8 | Topoisomerase I inhibitor (exatecan derivative) (DNA-targeting) | Interstitial lung disease Neutropenia Anemia Thrombocytopenia Nausea Left Ventricular Dysfunction | Normal tissue expression of antigen: Cardiac toxicity (Decrease LVEF) Payload-related: Gastrointestinal toxicity Myelosuppression Off target toxicity: Interstitial pneumonitis |
8. Sacituzumab govitecan (Trodelvy) | Trop-2 (Expressed in breast, cervix, colorectal, esophagus, gastric, certain lung cancers, squamous cell carcinoma of the oral cavity, ovary, pancreas, prostate, stomach, thyroid, urinary bladder, and uterus, also in several hematologic malignancies such as leukemia, extranodal nasal type lymphoma (ENK/TL) and NHL) | Cleavable acid-labile hydrazone (chemical) | 7.6 | SN-38 (active metabolite) of Irinotecan, topoisomerase-1 inhibitor (DNA-targeting) | Neutropenia Alopecia Anemia Vomiting Diarrhea Decreased Appetite Rash Hyperglycemia | Normal tissue expression of antigen: Skin rash Hyperglycemia Payload-related: Myelosuppression Diarrhea |
9. Loncastuximab Tesirine (Zynlonta) | CD19 (Expressed in normal and neoplastic B cells, as well as follicular dendritic cells) | Cleavable (Enzymatic) | 2.3 | SG3199, alkylating agent (Pyrrolobenzodiazepine dimer) (DNA-targeting) | Thrombocytopenia Increased gamma-glutamyltransferase Neutropenia Anemia Hyperglycemia Transaminase elevation Hypoalbuminemia Fluid retention Edema Musculoskeletal pain | Payload-related: Increased gamma-glutamyltransferase Fluid retention Myelosuppression |
10. Tisotumab vedotin (Tivdak) | Tissue factor (TF) (Expressed in cervical cancer, gastrointestinal, urogenital cancers, gliomas, melanomas, lung cancer, and breast cancer) | Cleavable (Enzymatic) | 4 | Monomethyl auristatin E (microtubule-targeting) | Anemia Leukopenia Peripheral Neuropathy Alopecia Epistaxis Conjunctival reactions Hemorrhage Increased creatinine Dry eye PT/INR/aPTT prolonged Rash | Normal tissue expression of antigen: Hemorrhagic complication and conjunctival reaction Payload-related: Peripheral sensory neuropathy Myelosuppression |
11. Mirvetuximab soravtansine-gynx (Elahere) | Folate factor alpha (FRα) (Expressed in solid tumors such as ovarian, lung and breast cancers) | Cleavable Disufide bond based (chemical) | 3.5 | DM4 (maytansinoid derivative) (microtubule-targeting) | Reversible ocular (uveitis and keratopathy) Pneumonitis Peripheral neuropathy | Payload-related: Peripheral neuropathy Myelosuppression Off target toxicity Ocular toxicity |
2.5. Linker
2.6. Cytotoxic Drugs
2.7. Conjugation
3. FDA Approved ADCs
3.1. Gemtuzumab Ozogamicin
3.2. Brentuximab Vedotin
3.3. Ado-Trastuzumab Emtansine
3.4. Inotuzumab Ozogamicin
3.5. Polatuzumab Vedotin Piiq
3.6. Enfortumab Vedotin
3.7. Trastuzumab Deruxtecan
3.8. Sacituzumab Govitecan
3.9. Loncastuximab Tesirine-Lpyl
3.10. Tisotumab Vedotin
3.11. Mirvetuximab Soravtansine-Gynx
4. ADCs Which Obtained FDA Approval and then Were Withdrawn from the Market
4.1. Belantamab Mafodotin-Blmf
4.2. Moxetumomab Pasudotox-Tdfk
ADC | FDA Approved Indications | FDA Approval Dates | Dose | NCCN Guideline Category | Clinical Trial |
---|---|---|---|---|---|
1. Gemtuzumab ozogamicin (Mylotarg) | Newly diagnosed CD33-positive acute myeloid leukemia (AML) to include pediatric patients 1 month and older | 1 September 2017 16 June 2020 (Approval for pediatric patients: 1 month and older) | Induction: 3 mg/m2 (up to one 4.5 mg vial) on days 1, 4, and 7 in combination with daunorubicin and cytarabine. Consolidation: 3 mg/m2 on day 1 (up to one 4.5 mg vial) in combination with daunorubicin and cytarabine. | Category 2B [29] | Phase III study (ALFA-0701) Phase III (AAML0531)-for pediatric patients. |
Relapsed or refractory (R/R) CD33-positive AML | 1 September 2017 | 3 mg/m2 on days 1, 4, and 7. | Category 2B [29] | Phase II (MyloFrance 1) | |
2. Brentuximab vedotin (Adcetris) | Classical Hodgkin lymphoma (cHL) after failure of ASCT or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates | 19 August 2011 (Accelerated approval) | 1.8 mg/kg by intravenous infusion every 3 weeks. (Maximum 16 cycles) | Category 2A [43] | Phase II |
cHL at high risk of relapse or progression as post-autologous hematopoietic stem cell transplantation (auto-HSCT) consolidation | 17 August 2015 | 1.8 mg/kg by intravenous infusion every 3 weeks, starting 30–45 days after transplantation. (Maximum 16 cycles) (Initiate within 4–6 weeks post-auto-HSCT or upon recovery from auto-HSCT) | Category 2A [43] | Phase III (AETHERA) | |
cHL previously untreated stage III or IV in combination with chemotherapy | 20 March 2018 | 1.2 mg/kg by intravenous infusion every 2 weeks. (Maximum for 12 doses) | Category 2A [43] | Phase III (ECHELON-1) | |
Relapsed or refractory systemic anaplastic large-cell lymphoma | 19 August 2011 (Accelerated approval) | 1.8 mg/kg by intravenous infusion every 3 weeks. (Maximum 16 cycles) | Category 2A [44] | Phase II | |
MF or pcALCL who had previously received one prior systemic therapy | 9 November 2017 | 1.8 mg/kg by intravenous infusion every 3 weeks until intolerance or disease progression. | Category 2A [44] | Phase III (ALCANZA) | |
Previously untreated systemic anaplastic large cell lymphoma (sALCL) | 16 November 2018 | 1.8 mg/kg by intravenous infusion every 3 weeks. | Category 1 [44] | Phase III (ECHELON-2) | |
Previously untreated other CD30-expressing peripheral T-cell lymphomas (PTCL), including angioimmunoblastic T-cell lymphoma, and PTCL not otherwise specified | 16 November 2018 | 1.8 mg/kg by intravenous infusion every 3 weeks with each cycle of chemotherapy for a maximum of 6 to 8 cycles. | Category 2A [44] | Phase III (ECHELON-2) | |
Pediatric patients with previously untreated high-risk classical Hodgkin lymphoma | 10 November 2022 | 1.8 mg/kg by intravenous infusion every 3 weeks with each cycle of chemotherapy for a maximum of 5 doses. | Not updated | Phase III (Study 7, AHOD1331, NCT02166463) | |
3. Ado- Trastuzumab emtansine (Kadcyla) | HER2-positive, metastatic breast cancer who have received prior therapy | 22 February 2013 | 3.6 mg/kg intravenous over 30 to 90 min on day 1 of a 21-day cycle until progression of disease or unacceptable toxicity | Category 2A [50] | Phase III (EMILIA trial) |
HER2-positive early breast cancer as a single agent, for the adjuvant treatment of patients with residual invasive disease after neoadjuvant taxane and trastuzumab-based treatment | 3 May 2019 | 3.6 mg/kg intravenously day 1 of a 21-day cycle for 14 cycles. | Category 1 [50] | Phase III (KATHERINE trial) | |
4. Inotuzumab ozogamicin (Besponsa) | Adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL) | 17 August 2017 | Initial: 1.8 mg/m2 in 3 divided doses on day 1 (0.8 mg/m2), day 8 (0.5 mg/m2), and day 15 (0.5 mg/m2). If CR/Cri:1.5 mg/m2 in 3 divided doses of 0.5 mg/m2 on days 1, 8, and 15. No CR or Cri:1.8 mg/m2 in 3 divided doses with 0.8 mg/m2 on day 1, and 0.5 mg/m2 on days 8 and 15. | Category 2A [55,56] | Phase III (INTO-VATE ALL) |
5. Polatuzumab vedotin piiq (Polivy) | Adult patients in combination with bendamustine and rituximab for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma, not otherwise specified, after at least two prior therapies. | 10 June 2019 (accelerated approval) | 1.8 mg/kg every 21 days for 6 cycles in combination with bendamustine and a rituximab. | Category 2B [64] | Phase II trial |
6. Enfortumab vedotin -ejfv (Padcev) | Advanced or metastatic urothelial cancer in patients who have previously received a PD-1 or PD-L1 inhibitor and a platinum-containing chemotherapy | 9 July 2021 | 1.25 mg/kg (up to a maximum of 125 mg for patients ≥ 100 kg) administered as an intravenous infusion over 30 min on days 1, 8, and 15 of a 28-day cycle until disease progression or unacceptable toxicity. | Category 2A [71] | Phase III study (EV-301) |
Advanced or metastatic urothelial cancer in patients who are ineligible for cisplatin-containing therapy and have previously received one or more prior lines of therapy | 9 July 2021 | Category 2A [71] | Phase III study (EV-301) | ||
Locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy as a first line in combination with pembrolizumab | 3 April 2023 (Accelerated approval) | 1.25 mg/kg intravenously over the course of 30 min on days 1 and 8 of each 21-day treatment cycle followed by pembrolizumab, intravenously at a dose of 200 mg on day 1 of each cycle about 30 min after enfortumab vedotin. | Not yet updated | Phase Ib/II (EV-103/Keynote-869) | |
7. Fam-Trastuzumab deruxtecan-nxki (Enhertu) | Unresectable or metastatic HER2-positive breast cancer who have received a prior anti-HER2-based regimen either in the metastatic setting, or in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within 6 months of completing therapy. | 4 May 2022 | 5.4 mg/kg IV day 1 every 21 days till disease progression or unacceptable toxicity. | Category 1 [80] | Phase III (DESTINY- Breast03) |
Unresectable or metastatic HER2-low (IHC 1+ or IHC 2 + /ISH-) breast cancer who have received a prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy | 5 August 2022 | Category 1 [80] | Phase III (DESTINY- Breast04) | ||
Locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen | 15 January 2021 | 6.4 mg/kg IV day 1 every 21 days till disease progression or unacceptable toxicity. | Category 2A [81] | Phase II (DESTINY-Gastric01) | |
Unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating HER2 (ERBB2) mutations and who have received a prior systemic therapy | 11 August 2022 (accelerated approval) | 5.4 mg/kg IV day 1 every 21 days till disease progression or unacceptable toxicity. | Category 2A [82] | Phase II (DESTINY-Lung02) | |
8. Sacituzumab govitecan -hziy (Trodelvy) | Adult patients with unresectable locally advanced or metastatic triple-negative breast cancer who have previously received two or more systemic therapies, with at least one therapy for metastatic disease | 7 April 2021 | 10 mg/kg once weekly on days 1 and 8 of a 21-day treatment cycle until disease progression or unacceptable toxicity. | Category 2A [90,91] | Phase III (ASCENT) |
Adult patients with locally advanced or metastatic urothelial cancer who have previously received a PD-1 or PD-L1 inhibitor | 13 April 2021 | Category 2A [90,92] | Phase II (TROPHY trial) | ||
Adult patients with unresectable, locally advanced or metastatic, hormone receptor (HR)-positive, HER2-negative breast cancer who have received endocrine-based therapy and at least two additional systemic therapies in the metastatic setting | 3 February 2023 | Not yet updated | Phase III (TROPiCS-02) | ||
9. Loncastuximab Tesirine-lpyl (Zynlonta) | Adult patients with relapsed or refractory large B-cell lymphoma after at least two lines of systemic therapy, including diffuse large B-cell lymphoma not otherwise specified, diffuse large B-cell lymphoma arising from low grade lymphoma, and high-grade B-cell lymphoma | 23 April 2021 (Accelerated approval) | 0.15 mg/kg every 3 weeks for 2 cycles, administered on day 1 of each cycle (every 3 weeks), and 0.075 mg/kg every 3 weeks for subsequent cycles. | Category 2A [104,106,107] | Phase II (LOTIS-2) |
10. Tisotumab vedotin-tftv (Tivdak) | Adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy | 20 September 2021(Accelerated approval) | 2 mg/kg given as an intravenous infusion over 30 min every 3 weeks until disease progression or toxicity. | Category 2A [113,114] | Phase II (InnovaTV 204) |
11. Mirvetuximab soravtansine-gynx (Elahere) | Folate receptor α positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer for patients who have received 1 to 3 previous systemic treatment regimens | 14 November 2022 (Accelerated approval) | 6 mg/kg intravenous administered once every 3 weeks until disease progression or unacceptable toxicity. | Not updated | Phase III single- arm study (SORAYA) |
5. Unique Toxicities of ADCs
6. Challenges
7. Future Directions
7.1. Improvement of ADC Design and Delivery
7.2. New Payloads with Immunotherapy Property or Radiation Property
8. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Gogia, P.; Ashraf, H.; Bhasin, S.; Xu, Y. Antibody–Drug Conjugates: A Review of Approved Drugs and Their Clinical Level of Evidence. Cancers 2023, 15, 3886. https://doi.org/10.3390/cancers15153886
Gogia P, Ashraf H, Bhasin S, Xu Y. Antibody–Drug Conjugates: A Review of Approved Drugs and Their Clinical Level of Evidence. Cancers. 2023; 15(15):3886. https://doi.org/10.3390/cancers15153886
Chicago/Turabian StyleGogia, Pooja, Hamza Ashraf, Sidharth Bhasin, and Yiqing Xu. 2023. "Antibody–Drug Conjugates: A Review of Approved Drugs and Their Clinical Level of Evidence" Cancers 15, no. 15: 3886. https://doi.org/10.3390/cancers15153886
APA StyleGogia, P., Ashraf, H., Bhasin, S., & Xu, Y. (2023). Antibody–Drug Conjugates: A Review of Approved Drugs and Their Clinical Level of Evidence. Cancers, 15(15), 3886. https://doi.org/10.3390/cancers15153886