Overview of ADC Drugs Approved Globally

In the early 20th century, Paul Ehrlich first proposed the famous “magic bullet” theory, suggesting that drugs could be developed to specifically target pathogens without affecting normal tissues and cells. Subsequently, the concept of antibody-drug conjugates (ADCs) was introduced, combining the target specificity of monoclonal antibodies with the anti-tumor properties of cytotoxic molecules. After decades of attempts, the development of ADCs achieved substantial success with the approval of Mylotarg (Gemtuzumab Ozogamicin), an ADC targeting CD33, in 2000.

Currently, there are 15 ADCs approved globally, including Pfizer’s Mylotarg, Besponsa; Roche’s Kadcyla, Polivy; AstraZeneca’s Lumoxiti, Enhertu; Seagen/Takeda’s Adcetris; Seagen/Astellas’ Padcev; Seagen/Genmab’s Tivdak; GSK’s Blenrep; Gilead’s Trodelvy; Rakuten Medical’s Akalux; ADCTherapeutics’ Zynlonta; Rongchang Biologics’ Disitamab; and ImmunoGen/East China Pharmaceutical’s Elahere. These drugs are used to treat conditions such as lymphoma, leukemia, breast cancer, multiple myeloma, head and neck cancer, and urothelial carcinoma.

Mylotarg® (gemtuzumab ozogamicin, Gemtuzumab)

Indication: Acute Myeloid Leukemia (AML)

Developer: Pfizer

Target: CD33

It consists of a humanized anti-CD33 monoclonal antibody, calicheamicin, and a cleavable linker. After binding to the CD33 antigen, the cytotoxin is internalized and released, inducing double-strand DNA breaks and cell death.

The world’s first marketed ADC. Approved by the FDA in 2000 for the treatment of acute myeloid leukemia (AML). Due to safety issues arising from unstable linkers and severe toxicity reactions caused by premature release of the cytotoxin, it was voluntarily withdrawn from the market in 2010.

Subsequently, Pfizer supplemented clinical evidence (three clinical trials: ALFA-0701, AML-19, MyloFrance-1), adjusted the specifications from the original 5mg/vial to 4.5 mg/vial, and modified the dosing regimen, reducing the recommended dose from 9mg/m² to 3mg/m², and resubmitted the application to the FDA.

In 2017, Mylotarg® was approved and re-marketed for the treatment of newly diagnosed acute myeloid leukemia (AML) positive for myeloid differentiation antigen (CD33) in adults, and for relapsed or refractory AML positive for CD33 in children aged ≥2 years and adults.

Adcetris® (brentuximab vedotin, Brentuximab, 安适利®)

Indication: Hodgkin Lymphoma / Systemic Anaplastic Large Cell Lymphoma

Developer: Takeda and Seattle Genetics

Target: CD30

It is an ADC targeting CD30, consisting of a chimeric IgG1 antibody cAC10, MMAE, and a protease-cleavable linker. After internalization, the proteinase releases MMAE, which induces cell cycle arrest and apoptosis by disrupting the microtubule system. Due to the bystander effect of MMAE, BV is also effective in heterogeneous tumors expressing CD30.

Approved by the FDA in August 2011 for the treatment of Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (sALCL).

In China, it was approved by the NMPA in May 2020 for the treatment of relapsed or refractory sALCL and CD30-positive HL patients, becoming the second ADC approved for marketing in the country.

In 2021, it was approved in the EU as a first-line treatment for CD30-expressing sALCL, becoming the first ADC approved for first-line treatment globally.

Brentuximab vedotin is a representative drug of the second-generation ADC, using human-mouse chimeric antibodies or humanized monoclonal antibodies instead of mouse-derived monoclonal antibodies, which reduces immunogenicity and enhances tumor targeting, and the linker used is also more stable. Its disadvantage is that there are many naked antibodies, which compete with conjugates for antigen binding sites, affecting efficacy. A high drug/antibody ratio (DAR) can lead to antibody aggregation, accelerated clearance, and increased non-specific toxicity.

Brentuximab carries an average of 4 MMAE molecules, with a drug/antibody ratio (DAR) of 4 and a molecular weight of approximately 153kDa.

Kadcyla® (ado-trastuzumab emtansine, Herceptin, 赫赛莱®)

Indication: Breast Cancer

Developer: Roche and ImmunoGen

Target: HER2

It is an ADC targeting HER2, consisting of a humanized anti-HER2 IgG1 monoclonal antibody (trastuzumab), a small molecule cytotoxin DM1, and an uncleavable linker. It maintains high stability in systemic circulation and tumor microenvironment.

On February 22, 2013, the FDA approved Kadcyla® for the treatment of metastatic HER2-positive breast cancer patients who had previously received trastuzumab and taxane treatment.

On May 3, 2019, the FDA approved Kadcyla® as a single agent for adjuvant treatment of HER2-positive breast cancer patients with residual disease after neoadjuvant trastuzumab treatment.

In January 2020, NMPA approved Kadcyla® for the treatment of HER2-positive early breast cancer patients with residual invasive lesions after neoadjuvant treatment based on taxane combined with trastuzumab, and for patients with unresectable locally advanced or metastatic breast cancer. It is the first ADC approved for marketing in China and the first ADC approved globally for solid tumors.

Kadcyla® is the most commercially successful ADC. In 2021, the global ADC market exceeded $5.2 billion, with Kadcyla® accounting for half of the market, with sales reaching $2.17 billion.

Kadcyla carries an average of 3.5 DM1 molecules per antibody, with a molecular weight of approximately 148,781 Da.

Besponsa® (inotuzumab ozogamicin, Inotuzumab, 贝博萨®)

Indication: BCP-ALL

Developer: Pfizer

Target: CD22

It is a humanized anti-CD22 monoclonal antibody conjugated to calicheamicin through an acid-labile hydrazone linker. CD22 is an endocytic receptor and a specific marker for B-cell acute lymphoblastic leukemia (ALL), expressed in over 90% of B-cell malignancy patients. Once the ADC binds to the CD22 receptor, the complex is internalized into target cells, triggering the release of calicheamicin, which induces apoptosis by binding to the minor groove of the DNA double helix and causing site-specific double-strand DNA cleavage.

It was approved by the EMA in June 2017 for the treatment of adult patients with relapsed or refractory precursor B-cell acute lymphoblastic leukemia (ALL).

In August 2017, it was approved by the FDA for the treatment of adult patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia. This is the first antibody-drug conjugate targeting CD22 approved by the FDA.

In December 2021, it was launched in China, becoming the fourth ADC approved for marketing in the country. The NMPA approval was based on the submission of overseas clinical trial data B1931022 in China, waiving the requirement for local clinical trials. Post-marketing research (B1931034) is required after marketing.

Besponsa® is Pfizer’s second ADC, a third-generation ADC product with lower antibody immunogenicity, stronger targeting, higher cellular activity, and a more stable linker. The stability and uniformity of the ADC have also improved.

Besponsa has a molecular weight of approximately 160 kDa, with an average of 6 calicheamicin molecules per antibody, with a distribution range of 2 to 8.

Lumoxiti® (Moxetumomab pasudotox, Moxetumomab)

Indication: Adult patients with relapsed or refractory hairy cell leukemia (HCL)

Developer: AstraZeneca

Target: CD22

It consists of an anti-CD22 monoclonal antibody covalently linked to a 38 kDa fragment of Pseudomonas exotoxin A (PE38). The Fv portion of the immunotoxin binds to CD22, and after internalization, induces apoptosis through ADP-ribosylation of the diphenylalanine residue in elongation factor-2 (EF-2).

It was approved by the FDA in September 2018 for the treatment of adult patients with relapsed or refractory hairy cell leukemia (HCL).

In February 2021, it was approved by the EMA. However, five months later, in July of the same year, the EMA announced the withdrawal of its marketing authorization in the EU.

Due to very low clinical use, AstraZeneca permanently withdrew Lumoxiti from the US market in July 2023. Both withdrawals were for commercial considerations, not safety issues.

Polivy® (polatuzumab vedotin, Polatuzumab, 优罗华®)

Indication: Diffuse Large B-cell Lymphoma

Developer: Roche

Target: CD79b

It is an ADC composed of an anti-CD79b monoclonal antibody, a protease-cleavable linker, and MMAE. CD79b is a B-cell-specific surface protein that is highly expressed in over 90% of B-cell non-Hodgkin lymphomas, such as diffuse large B-cell lymphoma and follicular lymphoma. After binding to the antibody, CD79b is rapidly internalized and delivered to lysosomes. Therefore, CD79b is an ideal target for the treatment of these lymphomas.

On June 11, 2019, it received accelerated approval from the FDA for the treatment of adult patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) after at least two prior therapies. Subsequently, it was approved in the EU and Japan in January and March 2021, respectively.

In January 2023, Polivy® received formal approval from the National Medical Products Administration (NMPA) in China for the indication of: in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone for the treatment of adult patients with previously untreated diffuse large B-cell lymphoma (DLBCL); and in combination with bendamustine and rituximab for the treatment of relapsed or refractory diffuse large B-cell lymphoma adult patients who are not suitable for hematopoietic stem cell transplantation.Polivy® is the only innovative targeted drug approved for first-line treatment of DLBCL in China in over 20 years.

Compared with traditional treatment regimens, Polivy® significantly improves clinical outcomes for patients, representing the first new treatment option in 20 years that significantly improves outcomes for relapsed or refractory diffuse large B-cell lymphoma.

Thus, Polivy® has been granted “orphan drug designation” in the US, “breakthrough therapy designation” by the FDA, and “priority medicine designation” by the EMA in the EU.

Polivy® has a drug/antibody ratio (DAR) of 3-4 and a molecular weight of approximately 150 kDa.

Enhertu® (fam-trastuzumab deruxtecan-nxki, Enhertu, 优赫得®)

Indication: Gastric Cancer, Metastatic Gastric Cancer, Metastatic Breast Cancer

Developer: AstraZeneca; Daiichi Sankyo

Target: HER2

Enhertu® is a representative of the third generation of ADCs, consisting of trastuzumab targeting HER2, a cleavable tetrapeptide linker, and a cytotoxic topoisomerase I inhibitor. Studies have shown that T-DXd is effective against both HER2-high and low-expressing tumor cells or HER2-mutated tumor cells, possibly due to: 1) T-DXd having a DAR value of up to 8, thus having an efficient payload; 2) the released payload having high membrane permeability, allowing it to enter adjacent tumor cells and produce a bystander effect; 3) the novel tetrapeptide-based linker having high stability in plasma.

In December 2019, Enhertu was granted accelerated approval by the FDA for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received prior HER2-targeted therapy.

In March 2022, a domestic marketing application was officially submitted and in May it was included in the priority review list, with the first indication being: treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received one or more prior anti-HER2 therapies.

Enhertu® has shown remarkable efficacy in treating HER2-positive metastatic breast cancer, representing a rare significant advance in ADC drug development in recent years, making HER2 the hottest ADC drug target currently.Enhertu® is the first and currently the only ADC with head-to-head comparison in second-line treatment for HER2-positive advanced breast cancer, achieving positive results.

According to market forecasts from Natrue’s subsidiary, Enhertu is expected to reach sales of $6.2 billion by 2026, capturing 40% of the global ADC market share. It may replace Kadcyla, becoming the new “king of drugs” among ADCs.

Padcev® (enfortumab vedotin, Enfortumab)

Indication: Urothelial Carcinoma

Developer: Seagen; Astellas

Target: Nectin-4

It is an ADC targeting Nectin-4, consisting of a human monoclonal antibody targeting Nectin-4, a protease-cleavable linker, and MMAE. Nectin-4 is a cell adhesion molecule that is overexpressed in 97% of urothelial carcinomas and is associated with tumor growth and proliferation.

Nectin-4 is expressed at very low levels in normal adult tissues, but is highly expressed in various tumor cells, such as urothelial carcinoma, bladder cancer, breast cancer, ovarian cancer, gastric cancer, hepatocellular carcinoma, and pancreatic cancer, being closely related to tumor occurrence and metastasis. It can promote tumor cell proliferation, differentiation, migration, and invasion by activating the PI3K/AKT pathway. Thus, Nectin-4 has become an important target for the diagnosis and treatment of many solid tumors.

In December 2019, the FDA granted accelerated approval for Padcev® for adult patients with locally advanced or metastatic urothelial carcinoma who have previously received treatment with a PD-1 inhibitor or PD-L1 inhibitor and platinum-based chemotherapy.

Padcev® is the first ADC approved for the treatment of urothelial carcinoma and the first drug approved targeting Nectin-4.

Trodelvy® (sacituzumab govitecan, Sacituzumab, 拓达维®)

Indication: Triple-Negative Breast Cancer

Developer: Gilead

Target: Trop-2

It is an ADC targeting Trop-2, composed of an antibody linked to SN-38 via an acid-labile hydrazone linker. SN-38 is a topoisomerase-1 inhibitor and an active metabolite of the chemotherapeutic drug irinotecan. After administration, the ADC binds to Trop-2 on tumor cells and promotes the release of SN-38, causing DNA damage and leading to cell cycle arrest. Due to the membrane permeability of SN-38, it can stimulate the anti-tumor effect in nearby cells without being internalized, producing a bystander effect.

TROP-2, a transmembrane glycoprotein, is overexpressed in various tumor tissues including breast cancer, gastric cancer, non-small cell lung cancer, small cell lung cancer, colon cancer, and pancreatic cancer, especially in triple-negative breast cancer, where the expression rate exceeds 90%.

In April 2020, Trodelvy® received accelerated approval from the FDA for the treatment of adults with metastatic triple-negative breast cancer who have previously received two or more therapies.

In June 2022, the NMPA approved Trodelvy® for adult patients who have previously received at least two systemic therapies, of which at least one therapy was for metastatic disease.

Blenrep® (belantamab mafodotin, Belantamab, 玛贝妥单抗)

Indication: Multiple Myeloma

Developer: GSK

Target: BCMA

It is an lgG antibody targeting B-cell maturation antigen (BCMA), conjugated to MMAF via an uncleavable maleimidomethylcyclopropane (MC) linker. BCMA is a cell surface protein expressed abundantly on malignant plasma cells, making it an important target for the treatment of multiple myeloma. Once belantamab maodotin binds to BCMA, the complex is internalized and degraded in lysosomes, releasing MMAF, inducing growth arrest and apoptosis.

In August 2020, the FDA granted accelerated approval for Blenrep® for adult patients with relapsed or refractory multiple myeloma who have received at least four prior therapies, including anti-CD38 monoclonal antibodies, immunomodulatory agents, and proteasome inhibitors.

In November 2022, the confirmatory Phase III DREAMM-3 trial of Blenrep® was declared a failure, being a head-to-head superiority trial comparing the efficacy of Blenrep monotherapy with pomalidomide plus low-dose dexamethasone (PomDex). In December of the same year, Blenrep® was withdrawn from the US market, becoming the fastest drug to be withdrawn after FDA’s accelerated approval.

However, this does not mean that GSK has stopped the development of this drug; the DREAMM series of clinical studies have not been paused, and GSK is exploring other potential benefits through combination therapy.

Akalux® (Cetuximab Sarotalocan Sodium, Cetuximab)

Indication: Head and Neck Cancer

Developer: Rakuten

Target: EGFR

It consists of an anti-EGFR antibody cetuximab conjugated to a photosensitizer IR700.

In September 2020, it received formal approval from the Japanese Ministry of Health, Labor and Welfare for the treatment of unresectable malignant tumors of the head and neck, also becoming the world’s first photodynamic therapy ADC, requiring combined use with the BioBlade laser system during treatment.

Akalux® binds to the EGFR antibody on the surface of cancer cells, using near-infrared light to irradiate the tumor site, activating the conjugated dye locally and destroying the tumor cell membrane already bound to the chemical agent, thereby achieving the goal of killing cancer cells.

Zynlonta® (Loncastuximab tesirine, Loncastuximab)

Indication: LBCB

Developer: ADCTherapeutics

Target: CD19

It is an ADC targeting CD19, conjugated to a cytotoxic alkylating agent SG3199 via a cleavable enzymatic linker. SG3199 is a synthetic PBD dimer that prevents cell division by promoting the formation of DNA interstrand cross-links, exhibiting potent cytotoxic effects.

On April 23, 2021, Zynlonta® received accelerated approval from the FDA for the treatment of patients with diffuse large B-cell lymphoma (DLBCL).

In December 2022, Zynlonta® received conditional approval from the European Medicines Agency (EMA).

Furthermore, the CDE website shows that in July 2023, Linglu Pharmaceuticals applied for the marketing of injectable Taloncastuximab (Application No: JXSS2300057), which is also the first CD19 ADC applied for marketing in China.

Disitamab Vedotin (爱地希®)

Indication: Gastric Cancer, Urothelial Carcinoma

Developer: Rongchang

Target: HER2

It consists of a novel humanized anti-HER2 antibody with higher affinity, a cleavable linker, and the microtubule inhibitor MMAE. Its mechanism includes inhibiting the HER2 signaling pathway and the cytotoxicity of MMAE.

In June 2021 and December 2021, Disitamab was approved by the NMPA for the treatment of HER2-overexpressing locally advanced or metastatic gastric cancer patients who have received at least two systemic chemotherapy regimens, as well as for the treatment of locally advanced or metastatic urothelial carcinoma with a score of 2+ or 3+.

In addition to the two approved indications, Rongchang Biologics is also conducting multiple clinical studies targeting solid tumors, including breast cancer (BC), and is exploring treatments for other common cancers that overexpress HER2, such as non-small cell lung cancer (NSCLC), biliary tract cancer (BTC), and melanoma.

Tivdak® (tisotumab vedotin-tftv, Tisotumab)

Indication: Cervical Cancer

Developer: Genmab

Target: TF

It is an ADC composed of a monoclonal antibody targeting tissue factor (TF-011), a cleavable mc-VC-PABC linker, and MMAE. Studies have shown that TF is highly expressed in cervical cancer tissues compared to normal cervical tissues. Once vedotin binds to TF, MMAE is delivered into the cells, blocking microtubule polymerization and terminating cell division.

In September 2021, the FDA granted accelerated approval for Tivdak for the treatment of adult patients with recurrent or metastatic cervical cancer who have disease progression during or after chemotherapy. Tivdak® is the first ADC approved for the treatment of recurrent or metastatic cervical cancer patients with disease progression during or after chemotherapy.

Elahere (mirvetuximab soravtansine-gynx, Mirvetuximab)

Indication: Ovarian Cancer

Developer: ImmunoGen, East China Pharmaceutical

Target: FRα

It is a FRα-targeting ADC composed of a humanized IgG1 anti-FRα monoclonal antibody M9346A, an anti-microtubule agent DM4 (a derivate of Maytansine), and a linker. FRα is highly expressed in 72%-100% of mesothelioma, 35%-68% of triple-negative breast cancer, 76%-89% of ovarian cancer, and 14%-74% of non-small cell lung cancer patient samples.

In November 2022, it received accelerated approval from the FDA as a monotherapy for the treatment of adult patients with epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer who have received one to three prior systemic treatment regimens and are FRα-positive and platinum-resistant.

Conclusion

This overview covers the 15 ADCs approved globally. Although only Disitamab® comes from China, it demonstrates that Chinese innovative pharmaceutical companies are no longer outsiders or bystanders but participants and guests at the table. While the global biopharmaceutical industry is still in a winter phase, many Chinese companies persistently pursuing original innovation are still forging ahead. However, the most challenging moments have passed, and the spring of original innovative drugs from China has quietly arrived.

Source:

1. BiG Bio Innovation Society: Series on Marketed ADCs

2. Packaging appearance of 15 ADC drugs approved globally. Antibody Circle. 2024-04-01

3. Overview: Domestic ADCs and Bispecific Antibodies. PharmaWto. 2023-08-17

4. Review and Future Prospects of Approved ADC Drugs. Biopharmaceutical Mover. 2024-04-11

5. 2023 Year-End Review: ADC Drugs Propel Leap in Cancer Treatment Progress! Overview of ADC Drugs Marketed Globally. Dongdong Cancer Circle. 2023-12-23

6. Summary of ADC Drugs (Antibody-Drug Conjugates) Approved for Marketing in China. Lidocaine vivi. 2024-02-26

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