Overview of ADC Drugs Approved Worldwide

In the early 20th century, Paul Ehrlich first proposed the famous “magic bullet” theory, suggesting that drugs could be developed to specifically target pathogenic structures without harming 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 ADC drugs approved worldwide, including Pfizer’s Mylotarg and Besponsa, Roche’s Kadcyla and Polivy, AstraZeneca’s Lumoxiti and Enhertu, Seagen/Takeda’s Adcetris, Seagen/Astellas’ Padcev, Seagen/Genmab’s Tivdak, GlaxoSmithKline’s Blenrep, Gilead’s Trodelvy, Rakuten Medical’s Akalux, ADCTherapeutics’ Zynlonta, Rongchang Bio’s Disitamab Vedotin, and ImmunoGen/East China Pharmaceutical’s Elahere. The therapeutic areas covered include lymphoma, leukemia, breast cancer, multiple myeloma, head and neck cancer, and urothelial carcinoma.

Overview of ADC Drugs Approved Worldwide

Mylotarg® (gemtuzumab ozogamicin, Gemtuzumab)

Indication: Acute Myeloid Leukemia (AML)

Developing Company: 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 First ADC Approved Globally. It received accelerated approval from the FDA in 2000 for the treatment of Acute Myeloid Leukemia (AML). Due to safety concerns arising from unstable linkers and severe toxicity from early release of the cytotoxin, it was voluntarily withdrawn from the market in 2010.

Subsequently, Pfizer supplemented and updated 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, recommending a dosage adjustment from 9mg/m² to 3mg/m², and resubmitted an 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, 维布妥昔单抗, 安适利®)

Indication: Hodgkin Lymphoma / Systemic Anaplastic Large Cell Lymphoma

Developing Company: Takeda and Seattle Genetics

Target: CD30

It is an ADC targeting CD30, composed of a chimeric lgG1 antibody cAC10, MMAE, and a cleavable linker. After internalization, the protease cleaves and 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, it is used 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 patients with relapsed or refractory sALCL and CD30 positive HL, 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, reducing immunogenicity and enhancing tumor targeting, and the linker used is also more stable. Its disadvantage is that there are many naked antibodies, which compete with the conjugates for antigen binding sites, affecting efficacy. A high drug-to-antibody ratio (DAR) can cause antibody aggregation, accelerated clearance, and increased non-specific toxicity.

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

Kadcyla® (ado-trastuzumab emtansine, 恩美曲妥珠单抗, 赫赛莱®)

Indication: Breast Cancer

Developing Company: Roche and ImmunoGen

Target: HER2

It is an ADC targeting HER2, composed of a humanized anti-HER2 IgG1 monoclonal antibody (trastuzumab), a small molecule cytotoxin DM1, and an non-cleavable linker. It maintains high stability in circulation and the 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 therapy.

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 therapy.

In January 2020, NMPA approved Kadcyla® for adjuvant treatment of HER2 positive early breast cancer patients with residual invasive lesions after neoadjuvant therapy based on taxanes combined with trastuzumab, and for locally advanced or metastatic breast cancer patients who are not amenable to surgery. It is the first ADC approved 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 that, with sales reaching $2.17 billion.

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

Besponsa® (inotuzumab ozogamicin, 奥加伊妥珠单抗, 贝博萨®)

Indication: BCP-ALL

Developing Company: Pfizer

Target: CD22

It is a humanized anti-CD22 monoclonal antibody conjugated to calicheamicin via 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 malignancies. Once the ADC binds to the CD22 receptor, the complex is internalized into the target cell, triggering the release of calicheamicin, which induces apoptosis by binding to the minor groove of DNA 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 adults 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’s approval was based on the submission of overseas clinical trial data B1931022 in China, exempting the requirement for a domestic registration clinical trial. After marketing, post-marketing research (B1931034) is required.

Besponsa® is Pfizer’s second ADC and third-generation ADC product, with lower antibody immunogenicity, stronger targeting, higher cellular activity, and improved stability and hydrophilicity of the small molecule cytotoxic drug, resulting in better stability and uniformity of the ADC.

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

Lumoxiti® (Moxetumomab pasudotox, 帕西妥莫单抗)

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

Developing Company: AstraZeneca

Target: CD22

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

It received FDA approval 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 usage, AstraZeneca permanently withdrew Lumoxiti from the U.S. market in July 2023. Both withdrawals were for commercial reasons, not safety issues.

Polivy® (polatuzumab vedotin, 泊洛妥珠单抗, 优罗华®)

Indication: Diffuse Large B-cell Lymphoma

Developing Company: 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, highly expressed in over 90% of B-cell non-Hodgkin lymphoma, such as diffuse large B-cell lymphoma and follicular lymphoma. After binding with the antibody, CD79b is rapidly internalized and delivered to the lysosome. Therefore, CD79b has become an ideal target for treating this type of lymphoma.

On June 11, 2019, it received accelerated approval from the FDA for use in combination with bendamustine and rituximab for the treatment of adult patients with relapsed or refractory 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. The indications are: In combination with rituximab, cyclophosphamide, doxorubicin, and prednisone for the treatment of previously untreated adult patients with diffuse large B-cell lymphoma (DLBCL); and in combination with bendamustine and rituximab for patients with relapsed or refractory diffuse large B-cell lymphoma 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 to traditional treatment regimens, Polivy® significantly improves clinical outcomes for patients and is the first new treatment regimen in 20 years to significantly improve outcomes for relapsed or refractory diffuse large B-cell lymphoma.

As a result, Polivy® has been granted “orphan drug status” in the U.S., “breakthrough therapy designation” by the FDA, and “priority medicine designation” by the EMA in the EU.

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

Enhertu® (fam-trastuzumab deruxtecan-nxki, 德喜曲妥珠单抗, 优赫得®)

Indication: Gastroesophageal Junction Cancer, Metastatic Gastric Cancer, Metastatic Breast Cancer

Developing Company: AstraZeneca; Daiichi Sankyo

Target: HER2

Enhertu® is a representative of the third-generation ADC, composed of trastuzumab targeting HER2, a cleavable tetrapeptide linker, and a topoisomerase I inhibitor. Studies show that T-DXd is effective against tumor cells with high or low expression of HER2 or HER2 mutations, which may include: 1) T-DXd has a DAR value as high as 8, thus having a highly effective payload; 2) The released payload has high membrane permeability, allowing it to enter adjacent tumor cells, producing a bystander effect; 3) The novel tetrapeptide-based linker has high stability in plasma.

In December 2019, Enhertu received accelerated approval from the FDA for the treatment of adults with unresectable or metastatic HER2 positive breast cancer who had previously received HER2 treatment.

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

Enhertu® has demonstrated 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 of HER2 positive advanced breast cancer, achieving positive results.

According to market forecasts from Natrue’s subsidiary, Enhertu is expected to reach $6.2 billion in sales by 2026, capturing 40% of the global ADC market share, potentially replacing Kadcyla and becoming the new generation of ADC “king of drugs”.

Padcev® (enfortumab vedotin, 恩诺单抗)

Indication: Urothelial Carcinoma

Developing Company: Seagen; Astellas

Target: Nectin-4

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

Nectin-4 is expressed at very low levels in healthy 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, closely related to tumor occurrence and metastasis, promoting tumor cell proliferation, differentiation, migration, and invasion through activation of the PI3K/AKT pathway. Therefore, Nectin-4 has become an important target for the diagnosis and treatment of many solid tumors.

In December 2019, the FDA accelerated the approval of Padcev® for adult patients with locally advanced or metastatic urothelial carcinoma who had 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 approved drug targeting Nectin-4.

Trodelvy® (sacituzumab govitecan, 戈沙妥珠单抗, 拓达维®)

Indication: Triple-Negative Breast Cancer

Developing Company: Gilead

Target: Trop-2

It is an antibody targeting Trop-2, conjugated to SN-38 via an acid-labile hydrazone linker. SN-38 is a topoisomerase-1 inhibitor and an active metabolite of the chemotherapy drug irinotecan. After administration, the ADC binds to Trop-2 on the tumor cells and promotes the release of SN-38, causing DNA damage and subsequent cell cycle arrest. Due to the membrane permeability of SN-38, it can stimulate the anti-tumor effects of 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 adult patients with metastatic triple-negative breast cancer who had previously received two or more systemic therapies.

In June 2022, NMPA approved Trodelvy® for adult patients who had previously received at least two systemic therapies, with at least one treatment targeting metastatic disease.

Blenrep® (belantamab mafodotin, 玛贝妥单抗)

Indication: Multiple Myeloma

Developing Company: GSK

Target: BCMA

It is an lgG antibody targeting B-cell maturation antigen (BCMA), conjugated to MMAF via an non-cleavable maleimidyl hexanoic (MC) linker. BCMA is a cell surface protein highly expressed on malignant plasma cells and is an important target for treating multiple myeloma. Once belantamab mafodotin binds to BCMA, the complex is internalized and degraded in the lysosome, releasing MMAF, inducing growth arrest and apoptosis.

In August 2020, the FDA accelerated the approval of Blenrep® for adult patients with relapsed or refractory multiple myeloma who had previously received at least four therapies, including an anti-CD38 monoclonal antibody, an immunomodulatory agent, and a proteasome inhibitor.

In November 2022, the confirmatory phase III DREAMM-3 trial of Blenrep® was announced to have failed, which was a head-to-head superiority trial comparing the efficacy of Blenrep monotherapy with pomalidomide combined with low-dose dexamethasone (PomDex). In December of the same year, Blenrep® was withdrawn from the U.S. market, making it the fastest drug to exit the market after “accelerated approval” by the FDA.

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

Akalux® (Cetuximab Sarotalocan Sodium, 沙西妥昔单抗)

Indication: Head and Neck Cancer

Developing Company: Rakuten

Target: EGFR

It is composed of an EGFR-targeting antibody cetuximab conjugated to a photosensitizer IR700.

In September 2020, it was officially approved by the Japanese Ministry of Health, Labour and Welfare for the treatment of unresectable malignant tumors in the head and neck, making it the first photodynamic therapy ADC approved globally, requiring combined use with the BioBlade laser system during treatment.

Akalux® binds to the EGFR antibody on the surface of cancer cells and uses near-infrared light to irradiate the tumor site, activating the conjugated dye locally and damaging the tumor cell membrane that has already bound to the chemical substance, thus achieving the goal of killing cancer cells.

Zynlonta® (Loncastuximab tesirine, 朗妥昔单抗)

Indication: LBCB

Developing Company: ADCTherapeutics

Target: CD19

It is an antibody targeting CD19, conjugated to a cleavable enzymatic linker with a cytotoxic alkylating agent SG3199. 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 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 Pharmaceutical’s injection of Taloncastuximab was submitted for marketing (Acceptance No.: JXSS2300057). This is also the first CD19 ADC submitted for marketing in the country.

爱地希® (Disitamab Vedotin, 维迪西妥单抗)

Indication: Gastric Cancer, Urothelial Carcinoma

Developing Company: Rongchang

Target: HER2

It consists of a novel humanized anti-HER2 antibody with higher affinity, a cleavable linker, and the microtubule inhibitor MMAE, with mechanisms including the inhibition of HER2 signaling pathways and the cytotoxicity of MMAE.

In June 2021 and December 2021, 爱地希® was approved by the NMPA for the treatment of locally advanced or metastatic gastric cancer (including gastroesophageal junction adenocarcinoma) 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 HER2 expression of 2+ or 3+. It is the first domestically approved ADC product.

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

Tivdak® (tisotumab vedotin-tftv, 替索单抗)

Indication: Cervical Cancer

Developing Company: Genmab

Target: TF

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

In September 2021, the FDA granted accelerated approval for Tivdak for 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 that progresses during or after chemotherapy.

Elahere (mirvetuximab soravtansine-gynx, 索米妥昔单抗)

Indication: Ovarian Cancer

Developing Company: ImmunoGen, East China Pharmaceutical

Target: FRα

It is an FRα-targeted ADC composed of an IgG1 subtype humanized anti-FRα 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 FDA accelerated approval as a monotherapy for the treatment of adults with FRα positive, platinum-resistant epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer who have previously received 1-3 systemic therapy regimens.

Conclusion

The above is an overview of the 15 ADC drugs approved worldwide. From the perspective of the original research areas, although only 爱地希® comes from China, it indicates that Chinese innovative pharmaceutical companies are no longer outsiders or spectators but participants and guests of honor. Although the winter of the global biopharmaceutical industry has not yet ended, many Chinese companies that persist on the path of original innovation are still forging ahead. However, the most difficult moments have passed, and the spring of original innovative drugs from China has quietly arrived.

Source:

1. BiG Bio-Innovation Society: ADC Series on the Market

2.Overview of 15 ADC Drugs Approved Worldwide. Antibody Circle. 2024-04-1

3. Overview of Domestic ADCs & Bispecific Antibodies. Pharmaceutical Exchange. 2023-08-17

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

5. 2023 Year-End Review: ADC Drugs Accelerate Cancer Treatment Progress! Overview of ADC Drugs Approved Worldwide. Dongdong Cancer Friends Circle. 2023-12-23

6.Summary of Domestic ADC Drugs (Antibody-Drug Conjugates). Lidoka vivi. 2024-02-26

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