Antibody-drug conjugates (ADCs) are a class of targeted therapies that link cytotoxic drugs (payloads) to monoclonal antibodies via chemical linkers. This design enables efficient and selective delivery of the cytotoxic agent to tumor cells, thereby exerting anti-cancer effects. In recent years, as ADC technology has matured, many of the limitations seen in early ADCs have been overcome, leading to a growing number of ADCs being approved.

As of 2025, a total of 18 ADC drugs have been approved globally.

Table: Summary of Approved ADC Drugs

1. Gemtuzumab ozogamicin (Mylotarg®)

Gemtuzumab ozogamicin (Mylotarg®), developed by Pfizer, is the world's first ADC approved for marketing. It is used for the treatment of CD33-positive acute myeloid leukemia (AML) in adults and children over 2 years old.

Structure

Mylotarg is composed of:

• • A humanized monoclonal antibody targeting the CD33 antigen on AML cells

• • A potent cytotoxic agent, N-acetyl-γ-calicheamicin

• • A cleavable hydrazone linker, which releases the drug inside cancer cells

Mechanism of Action

After Mylotarg® binds to CD33 on the surface of AML cells, the complex is internalized. The acidic environment inside the cell cleaves the linker, releasing calicheamicin, which induces double-stranded DNA breaks, leading to cell death.

Clinical Development & Approvals

• • 2000: FDA granted accelerated approval for older AML patients

• • 2010: Withdrawn due to safety concerns from early drug release and toxicity

• • 2017: Reapproved after dose adjustments (from 9 mg/m² to 3 mg/m²) and new supporting data from three clinical trials (ALFA-0701, AML-19, MyloFrance-1). Mylotarg® was approved for both newly diagnosed and relapsed/refractory CD33-positive AML.

2. Brentuximab Vedotin (Adcetris®)

Brentuximab vedotin, marketed as Adcetris®, was developed by Seagen Inc. in collaboration with Takeda Pharmaceutical Company. It is the second ADC approved for cancer treatment, targeting CD30-positive lymphomas such as Hodgkin’s lymphoma (HL), systemic anaplastic large cell lymphoma (sALCL) and relapsed/refractory diffuse large B-cell lymphoma (DLBCL).

Structure

Adcetris® is composed of:

• • A chimeric monoclonal antibody (cAC10) targeting CD30

• • A protease-cleavable dipeptide linker (mc-VC-PABC)

• • The cytotoxic payload monomethyl auristatin E (MMAE), a microtubule-disrupting agent

On average, each antibody carries four MMAE molecules (DAR = 4).

Mechanism of Action

Once Brentuximab vedotin binds to CD30 on cancer cells, it is internalized, and the linker is cleaved by intracellular proteases. This releases MMAE, which disrupts the microtubule network, causing cell cycle arrest and apoptosis.

Clinical Development & Approvals

• • 2011: FDA approval for relapsed/refractory HL and sALCL

• • 2018: FDA expanded approval for use in combination with CHP (cyclophosphamide, doxorubicin, prednisone) in newly diagnosed CD30-positive peripheral T-cell lymphoma (including sALCL)

• • 2022: FDA approved it for previously untreated high-risk pediatric Hodgkin lymphoma

• • 2025: FDA approved a combination regimen for relapsed/refractory diffuse large B-cell lymphoma (DLBCL)

3. Trastuzumab Emtansine (Kadcyla® )

Kadcyla® (ado-trastuzumab emtansine, also known as T-DM1), developed by Genentech (a member of the Roche Group) in collaboration with ImmunoGen, is an ADC approved for the treatment of HER2-positive breast cancer.

Structure

Kadcyla®  is composed of:

• • Trastuzumab, a humanized anti-HER2 IgG1 monoclonal antibody

• • The cytotoxic agent DM1 (a maytansine derivative)

• • A non-cleavable thioether linker

On average, each antibody is conjugated with 3.5 DM1 molecules。

Mechanism of Action

T-DM1 binds to HER2 receptors on the surface of tumor cells. After internalization, lysosomal degradation of the antibody releases DM1. DM1 then inhibits microtubule assembly, leading to cell cycle arrest and apoptosis, while minimizing damage to healthy cells.

Clinical Development & Approvals

• • 2013: FDA approval for HER2-positive metastatic breast cancer in patients previously treated with trastuzumab and taxanes

• • 2019: FDA approval for adjuvant treatment of patients with residual disease after neoadjuvant trastuzumab-based therapy

4. Inotuzumab Ozogamicin (Besponsa®)

Inotuzumab ozogamicin, marketed as Besponsa®, is an ADC designed to treat CD22-positive B-cell precursor acute lymphoblastic leukemia (BCP-ALL), both in adults and pediatric patients with relapsed or refractory disease.

Structure

Besponsa® is composed of:

• • A humanized IgG4 monoclonal antibody targeting CD22

• • An acid-labile hydrazone linker

• • The cytotoxic payload calicheamicin, a DNA-damaging agent

Each antibody carries an average of 6 calicheamicin molecules (DAR ≈ 6, range 2–8).

Mechanism of Action

Besponsa® binds to CD22 on malignant B-cells and is internalized. The acidic intracellular environment cleaves the hydrazone linker, releasing calicheamicin. This agent binds to the DNA minor groove, induces double-strand breaks, and initiates apoptosis.

CD22 is highly expressed in over 90% of B-cell ALL cases, making it an effective target for selective drug delivery.

Clinical Development & Approvals

• • June 2017: EMA approval for adults with relapsed/refractory BCP-ALL

• • August 2017: FDA approval for adults with relapsed/refractory BCP-ALL

• • 2024: FDA approval expanded to include pediatric patients with relapsed/refractory ALL

Besponsa® is considered a third-generation ADC, with enhanced stability, improved payload hydrophilicity, lower immunogenicity, and better tumor selectivity compared to earlier ADCs.

5. Moxetumomab pasudotox-tdfk (Lumoxiti®)

Moxetumomab pasudotox, marketed as Lumoxiti®, was developed by AstraZeneca and represents the first immunotoxin approved specifically for the treatment of relapsed or refractory hairy cell leukemia (HCL) in adults. It is a fusion protein-based therapeutic that targets CD22, a cell surface marker consistently expressed on malignant B-cells in HCL.

Structure

Lumoxiti® is composed of:

• • A recombinant single-chain variable fragment (scFv) antibody targeting CD22

• • A 38 kDa truncated fragment of Pseudomonas exotoxin A (PE38)

• • A linker mc-VC-PABC

The engineered protein selectively binds to CD22-positive cells and delivers the cytotoxic toxin directly into malignant B-cells.

Mechanism of Action

Upon binding to CD22, Lumoxiti® is internalized by receptor-mediated endocytosis. Inside the cell, PE38 catalyzes ADP-ribosylation of elongation factor-2 (EF-2), a critical protein for protein synthesis. This process halts translation and induces apoptotic cell death.

Clinical Development & Approvals

• • September 2018: FDA approval for adult patients with relapsed or refractory HCL after at least two prior systemic therapies

• • February 2021: EMA approval in the EU

• • July 2021: EMA withdrew marketing authorization due to low clinical uptake

• • July 2023: Voluntarily withdrawn from the U.S. market for commercial reasons (not safety-related)

Although no longer marketed, Lumoxiti® demonstrated high durable response rates and minimal residual disease (MRD) negativity in heavily pretreated HCL patients, with manageable toxicity.

6. Polatuzumab Vedotin (Polivy®)

Polatuzumab vedotin, marketed as Polivy®, was developed by Genentech (a member of the Roche Group). It is an ADC specifically designed to target CD79b, a B-cell-specific antigen highly expressed in most B-cell non-Hodgkin lymphomas, including diffuse large B-cell lymphoma (DLBCL). Polivy® represents a major advancement in the treatment of relapsed or refractory DLBCL, particularly for patients who are not eligible for stem cell transplant.

Structure

Polivy® consists of three main components:

• • A humanized monoclonal antibody targeting CD79b

• • A protease-cleavable linker (mc-VC-PABC)

• • The cytotoxic payload MMAE, a potent microtubule-disrupting agent

Each antibody is conjugated with approximately 3 to 4 MMAE molecules (DAR = 3–4).

Mechanism of Action

After binding to CD79b on the surface of malignant B-cells, Polatuzumab vedotin is rapidly internalized and trafficked to the lysosome. The linker is then cleaved by intracellular proteases, releasing MMAE inside the cell. MMAE disrupts the microtubule network, leading to cell cycle arrest and apoptosis. Additionally, Polivy® promotes degradation of the anti-apoptotic protein MCL-1 via the ubiquitin-proteasome pathway, enhancing cancer cell death.

Clinical Development & Approvals

• • June 2019: FDA granted accelerated approval in combination with bendamustine and rituximab for adult patients with relapsed/refractory DLBCL after at least two prior therapies

• • April 2023: FDA full approval for Polivy® in combination with R-CHP (rituximab, cyclophosphamide, doxorubicin, and prednisone) for previously untreated DLBCL

With its improved efficacy over traditional regimens, Polivy® is the first major therapeutic advance for DLBCL in nearly two decades.

7. Enfortumab Vedotin (Padcev®)

Enfortumab vedotin, marketed as Padcev®, is the first ADC approved for the treatment of urothelial cancer, specifically targeting Nectin-4—a cell adhesion molecule highly expressed in over 97% of urothelial carcinomas and several other solid tumors. Padcev® offers a novel therapeutic approach for patients with locally advanced or metastatic urothelial cancer (la/mUC), especially those who have progressed following platinum-based chemotherapy and immune checkpoint inhibitors.

Structure

Enfortumab vedotin is composed of:

• • A fully human monoclonal antibody targeting Nectin-4

• • A protease-cleavable linker (mc-VC-PABC)

• • The cytotoxic payload MMAE, a potent anti-mitotic agent

The average drug-to-antibody ratio (DAR) is approximately 3.8.

Mechanism of Action

After binding to Nectin-4 on tumor cells, Enfortumab vedotin is internalized and trafficked to lysosomes, where the linker is cleaved by intracellular proteases to release MMAE. MMAE disrupts the microtubule network by binding to tubulin, causing cell cycle arrest and apoptosis. Additionally, Nectin-4 plays a role in activating the PI3K/AKT signaling pathway, which is associated with tumor proliferation, survival, and metastasis—making it an ideal therapeutic target.

Clinical Development & Approvals

• • December 2019: FDA accelerated approval as monotherapy for adults with la/mUC who have previously received both a PD-1/PD-L1 inhibitor and platinum-containing chemotherapy

• • April 2023: FDA approval of Enfortumab vedotin + pembrolizumab (Keytruda®) for first-line treatment of la/mUC in patients ineligible for cisplatin-containing chemotherapy

• • December 2023: FDA full approval of the Enfortumab vedotin+ pembrolizumab (Keytruda®) combination as the first and only ADC plus PD-1 inhibitor therapy for advanced bladder cancer

Padcev® represents a significant advance in the management of advanced urothelial cancer, providing a targeted and effective treatment option for patients with limited alternatives.

8. Trastuzumab Deruxtecan (Enhertu®)

Trastuzumab deruxtecan, marketed as Enhertu®, is a next-generation HER2-targeted ADC co-developed by AstraZeneca and Daiichi Sankyo. Representing a major milestone in ADC innovation, Enhertu® is indicated for a wide range of HER2-expressing cancers, including breast cancer, gastric cancer, non-small cell lung cancer (NSCLC), and other HER2-positive solid tumors.

Structure

Enhertu® consists of:

• • A humanized monoclonal antibody (trastuzumab) that targets HER2

• • A cleavable tetrapeptide linker

• • A potent topoisomerase I inhibitor payload (a derivative of exatecan)

The ADC features a high drug-to-antibody ratio (DAR) of ~8, allowing for increased payload delivery per antibody molecule. The cytotoxic payload is membrane-permeable, enabling a strong bystander effect—killing neighboring tumor cells regardless of HER2 expression level. The linker also exhibits high stability in plasma, minimizing off-target toxicity.

Mechanism of Action

Once bound to HER2-expressing tumor cells, the ADC is internalized and trafficked to lysosomes, where the linker is cleaved to release the topoisomerase I inhibitor. This leads to DNA damage, cell cycle arrest, and apoptosis. Its membrane-permeable payload allows the drug to diffuse into nearby tumor cells, expanding its cytotoxic effect beyond the target cell.

Clinical Development & Approvals

• • December 2019: FDA accelerated approval for HER2-positive metastatic breast cancer patients previously treated with anti-HER2 therapy

• • January 2021: FDA approval for HER2-positive advanced gastric cancer

• • August 2022: First HER2-directed therapy approved for HER2-low metastatic breast cancer and HER2-mutant metastatic NSCLC

• • April 2024: Approved as the first tumor-agnostic HER2-directed therapy for previously treated HER2-positive solid tumors

• • January 2025: FDA approval for HER2-low or HER2-ultralow metastatic breast cancer

Its versatility across multiple subgroups of breast cancer, including HER2-positive, HR+/HER2-negative, and triple-negative types, combined with its long treatment duration, underline its significant potential in the oncology market. Enhertu® is regarded as one of the most transformative ADCs in recent oncology history.

9. Sacituzumab Govitecan (Trodelvy®)

Sacituzumab govitecan, marketed as Trodelvy®, is the first FDA-approved ADC targeting Trop-2, a transmembrane glycoprotein highly expressed in a variety of epithelial tumors. It is currently approved for the treatment of adult patients with metastatic triple-negative breast cancer (mTNBC) and HR+/HER2- metastatic breast cancer who have received prior systemic therapies.

Structure

Trodelvy® is composed of:

• • A humanized monoclonal antibody targeting Trop-2

• • SN-38, a potent topoisomerase I inhibitor and active metabolite of irinotecan

• • A cleavable, pH-sensitive CL2A linker that releases SN-38 in the tumor microenvironment

This ADC has a high drug-to-antibody ratio (DAR) of approximately 7–8, enhancing cytotoxic payload delivery to Trop-2–expressing cells.

Mechanism of Action

Following binding to Trop-2 on tumor cells, Trodelvy® is internalized and trafficked to lysosomes, where the CL2A linker is hydrolyzed, releasing SN-38. The payload then inhibits topoisomerase I, causing DNA damage, cell cycle arrest, and apoptosis. Due to the membrane permeability of SN-38, Trodelvy® also exerts a bystander effect, killing adjacent tumor cells regardless of Trop-2 expression.

Clinical Development & Approvals

• • April 2020: FDA accelerated approval for mTNBC after ≥2 prior therapies for metastatic disease

• • April 2021: FDA accelerated approval for metastatic urothelial cancer (withdrawn October 2024)

• • February 2023: FDA full approval for HR+/HER2- metastatic breast cancer after endocrine therapy and chemotherapy

Trodelvy® has shown significant clinical benefit in difficult-to-treat breast cancer populations, offering a targeted option with both direct tumor-killing activity and a bystander cytotoxic effect.

10. Belantamab Mafodotin (Blenrep®)

Belantamab mafodotin, marketed as Blenrep®, was developed by GlaxoSmithKline (GSK) and is the first ADC approved globally to target B-cell maturation antigen (BCMA). It was granted accelerated approval by the FDA in August 2020 for the treatment of adult patients with relapsed or refractory multiple myeloma (R/R MM) who had received at least four prior therapies, including a proteasome inhibitor, an immunomodulatory agent, and a CD38 monoclonal antibody.

Structure

Blenrep® is composed of:

• • A humanized IgG1 monoclonal antibody targeting BCMA

• • Monomethyl auristatin F (MMAF), a potent microtubule inhibitor

• • A non-cleavable maleimidocaproyl (mc) linker that stably connects the antibody and payload

This design ensures targeted delivery of MMAF to malignant plasma cells, minimizing systemic toxicity.

Mechanism of Action

Upon binding to BCMA, which is highly expressed on the surface of malignant plasma cells, the ADC is internalized and trafficked to lysosomes. Within the cell, the non-cleavable linker is degraded, releasing MMAF. The payload disrupts microtubule polymerization, leading to cell cycle arrest and apoptosis. Blenrep® also exhibits immune-mediated mechanisms such as antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis.

Clinical Development & Approvals

• • August 2020: FDA accelerated approval for heavily pretreated R/R MM

• • November 2022: Phase III DREAMM-3 trial did not meet its primary endpoint compared to PomDex; the FDA requested market withdrawal

• • December 2022: Voluntarily withdrawn from the U.S. market

Despite the setback, GSK continues to explore Blenrep® in combination therapies through the ongoing DREAMM clinical trial program, aiming to identify patient populations that may still benefit from this first-in-class BCMA-targeted ADC.

 11. Cetuximab Sarotalocan Sodium (Akalux®)

Akalux®, developed by Rakuten Medical, is a first-in-class ADC approved in Japan for the treatment of unresectable head and neck cancers. It represents a pioneering approach in cancer therapy known as photoimmunotherapy (PIT), combining targeted immunotherapy with light-activated cytotoxicity.

Structure

Akalux® is composed of:

• • Cetuximab, an EGFR-targeting monoclonal antibody

• • Linker-Payload: IRDye® 700DX (IR700), a photosensitive dye

The conjugate is designed to selectively bind to EGFR-expressing tumor cells, including those found in head and neck, esophageal, lung, colon, and pancreatic cancers.

Mechanism of Action

After intravenous administration, Akalux® binds to EGFR on the surface of tumor cells. When exposed to non-thermal red light (690 nm) via the BioBlade® Laser System, the IR700 dye becomes photoactivated, producing rapid, localized damage to the cancer cell membrane. This selective photochemical reaction leads to immediate necrotic cell death with minimal effect on surrounding healthy tissue.

Clinical Development & Approvals

• • September 2020: Approved by Japan’s MHLW for unresectable head and neck cancer, along with the BioBlade® Laser System.

As the first photoimmunotherapy-based drug globally approved, Akalux® marks a new frontier in precision oncology, offering a novel, minimally invasive treatment for solid tumors overexpressing EGFR.

12. Loncastuximab Tesirine (Zynlonta®)

Loncastuximab tesirine, marketed as Zynlonta®, is an innovative ADC developed by ADC Therapeutics. It is the first and only CD19-targeting ADC approved specifically for the treatment of relapsed or refractory large B-cell lymphoma (LBCL). The drug was granted accelerated approval by the U.S. FDA in April 2021 and received conditional approval from the European Medicines Agency (EMA) in December 2022.

Structure

Zynlonta® is composed of:

• • A humanized monoclonal antibody directed against CD19

• • A protease-cleavable valine-alanine dipeptide linker

• • SG3199, a synthetic pyrrolobenzodiazepine (PBD) dimer cytotoxic payload

This composition enables the precise delivery of a potent DNA-damaging agent to CD19-expressing malignant B cells.

Mechanism of Action

Once Zynlonta® binds to CD19 on the surface of tumor cells, it is internalized, and the linker is enzymatically cleaved within the lysosome, releasing SG3199. The PBD payload then induces DNA interstrand cross-linking, which prevents DNA replication and ultimately triggers apoptotic cell death. The PBD dimer is known for its high potency and ability to kill both dividing and non-dividing cells, making it especially effective against aggressive lymphomas.

Clinical Development & Approvals

• • April 2021: FDA accelerated approval for adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy

• • December 2022: Conditional approval by the EMA for similar indications in Europe

Zynlonta® offers a novel treatment option for patients with difficult-to-treat LBCL, particularly those who have failed prior lines of therapy. Its targeted approach and potent mechanism of action position it as a valuable addition to the evolving landscape of lymphoma therapeutics.

13. Disitamab Vedotin (Aidixi®)

Disitamab vedotin, marketed as Aidixi® and developed by RemeGen, represents a significant advancement in HER2-targeted therapy, offering a new treatment option for patients with HER2-overexpressing solid tumors. The drug received approval from China's National Medical Products Administration (NMPA) in June and December of 2021 for the treatment of HER2-positive gastric and urothelial cancers, respectively.

Structure

Aidixi® consists of:

• • A novel humanized anti-HER2 monoclonal antibody with enhanced binding affinity

• • A cleavable linker

• • MMAE, a potent microtubule-disrupting cytotoxic agent

This optimized structure allows for both effective HER2 signal blockade and precise delivery of a highly cytotoxic payload to tumor cells.

Mechanism of Action

Upon binding to HER2-overexpressing tumor cells, Disitamab vedotin is internalized and undergoes proteolytic cleavage within the lysosome, releasing MMAE. MMAE then binds to tubulin, disrupting microtubule dynamics and inducing cell cycle arrest followed by apoptosis. In addition, the antibody component blocks HER2-mediated signaling pathways, contributing further to its anti-tumor effects.

Clinical Development & Approvals

• • June 2021: NMPA approval for HER2-overexpressing (IHC 2+/3+) locally advanced or metastatic gastric cancer, including gastroesophageal junction adenocarcinoma, in patients who have received at least two prior systemic treatments

• • December 2021: NMPA approval for locally advanced or metastatic urothelial carcinoma with HER2 IHC 2+/3+ expression

RemeGen is actively expanding the clinical scope of Aidixi®, with ongoing studies in breast cancer (BC), NSCLC, biliary tract cancer (BTC), melanoma, and other HER2-expressing solid tumors.

14. Tisotumab Vedotin (Tivdak®)

Tisotumab vedotin, marketed as Tivdak®, is the first FDA-approved ADC specifically for adult patients with recurrent or metastatic cervical cancer whose disease has progressed on or after chemotherapy. This breakthrough therapy leverages a unique mechanism of action by targeting tissue factor (TF), a protein highly overexpressed in cervical cancer cells compared to normal tissue.

Structure

Tivdak® is composed of:

• • A fully human monoclonal antibody that targets tissue factor (TF/CD142)

• • A protease-cleavable mc-VC-PABC linker

• • The cytotoxic payload MMAE, a microtubule-disrupting agent

This structure ensures targeted delivery of the cytotoxin directly into TF-expressing cancer cells.

Mechanism of Action

After binding to tissue factor on the surface of tumor cells, Tivdak® is internalized, and MMAE is released through proteolytic cleavage. MMAE then disrupts microtubule polymerization, leading to mitotic arrest and apoptotic cell death. In addition to direct cytotoxicity, TF targeting may also influence the tumor microenvironment and angiogenesis.

Clinical Development & Approvals

• • September 2021: FDA granted accelerated approval for recurrent or metastatic cervical cancer in adult patients with disease progression during or after chemotherapy

• • April 29, 2024: FDA converted accelerated approval to full approval based on confirmatory trial results

Tivdak® remains the only ADC approved specifically for cervical cancer and continues to be explored in additional solid tumors where tissue factor is overexpressed.

15. Mirvetuximab Soravtansine (Elahere®)

Mirvetuximab soravtansine, marketed as Elahere®, is a first-in-class ADC approved for the treatment of adult patients with folate receptor alpha (FRα)-positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer who have received one to three prior systemic treatment regimens.

Structure

Elahere® is composed of:

• • A humanized anti-FRα monoclonal antibody (IgG1 subtype, M9346A)

• • A cleavable linker

• • The cytotoxic payload DM4, a maytansinoid microtubule inhibitor

This targeted ADC design allows selective delivery of the cytotoxin to tumor cells that overexpress FRα.

Mechanism of Action

Elahere® binds specifically to FRα on cancer cells, which are then internalized via receptor-mediated endocytosis. Once inside the cell, the linker is cleaved, releasing DM4. DM4 disrupts microtubule dynamics, resulting in cell cycle arrest and apoptosis.

FRα is minimally expressed in normal tissue but highly overexpressed in many epithelial tumors, including up to 89% of ovarian cancers, making it an ideal therapeutic target.

Clinical Development & Approvals

• • November 2022: FDA granted accelerated approval for Elahere® as monotherapy in FRα-positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer patients who received 1–3 prior systemic treatments

• • Elahere® represents a significant advancement in targeted therapies for ovarian cancer, especially in patients with limited treatment options. Ongoing trials continue to evaluate its efficacy in broader indications and combination regimens.

16. Sacituzumab Tirumotecan (Jiataile®)

Sacituzumab tirumotecan, marketed as Jiataile® is a next-generation ADC co-developed by Kelun-Biotech and Merck & Co. It is designed to treat patients with TROP2-expressing solid tumors, including triple-negative breast cancer (TNBC) and NSCLC.

Structure

Sacituzumab tirumotecan consists of three components:

• • A humanized monoclonal antibody targeting TROP2

• • A proprietary topoisomerase I inhibitor payload (KL610023)

• • A novel, hydrolyzable yet irreversible linker, with a drug-to-antibody ratio (DAR) of 7.4

This design enables efficient payload delivery and promotes a bystander killing effect, making it effective even in tumors with heterogeneous TROP2 expression.

Mechanism of Action

After binding to TROP2-expressing cancer cells, the sacituzumab antibody facilitates internalization of the ADC complex. Once inside the cell, the linker is cleaved to release KL610023, a potent topoisomerase I inhibitor that induces DNA damage and disrupts cell division, ultimately triggering apoptosis.

Additionally, KL610023 can diffuse into the tumor microenvironment and exert cytotoxic effects on neighboring tumor cells, a phenomenon known as the bystander effect, which enhances overall tumor-killing potential.

Clinical Development & Approvals

• • November 27, 2024: Approved by China’s NMPA for locally advanced or metastatic TNBC after at least two prior systemic treatments

• • March 10, 2025: Approved by NMPA for treatment of EGFR-mutant locally advanced or metastatic NSCLC following failure of EGFR-TKI and platinum-based chemotherapy

• • United States: Regulatory approval is still pending

Sacituzumab tirumotecan represents a promising advancement in the treatment of hard-to-treat cancers and underscores the growing importance of ADCs in precision oncology.

17. Datopotamab Deruxtecan (Datroway®)

Datopotamab deruxtecan, marketed as Datroway® (development code Dato-DXd), is an innovative ADC co-developed by Daiichi Sankyo and AstraZeneca. It is designed to target TROP2-expressing tumors, including hormone receptor (HR)-positive, HER2-negative breast cancer and EGFR-mutant NSCLC.

Structure

Datopotamab deruxtecan consists of three core components:

• • A humanized IgG1 monoclonal antibody targeting TROP2

• • A topoisomerase I inhibitor payload (DXd, a derivative of exatecan)

• • A tetrapeptide-based cleavable linker

The design leverages Daiichi Sankyo’s proprietary DXd ADC technology, enabling efficient intracellular release of the cytotoxic payload and promoting a robust bystander effect, even in tumors with variable TROP2 expression.

Mechanism of Action

Upon binding to TROP2-expressing tumor cells, Datroway® is internalized, and the linker is cleaved by lysosomal enzymes to release the DXd payload. DXd inhibits topoisomerase I, causing DNA double-strand breaks, disrupting replication, and ultimately inducing apoptosis.

Due to its membrane-permeable nature, DXd can also diffuse into the surrounding tumor microenvironment, killing neighboring cancer cells that may not express TROP2—an effect known as the bystander effect, which broadens the therapeutic impact.

Clinical Development & Approvals

• • December 2024: First global approval in Japan for unresectable or recurrent HR+/HER2- breast cancer after chemotherapy

• • January 2025: Approved by the U.S. FDA for unresectable or metastatic HR+/HER2- breast cancer following endocrine therapy and chemotherapy

Datopotamab deruxtecan (Datroway®) represents a significant advancement in TROP2-targeted therapy, offering new hope for patients with hard-to-treat breast and lung cancers. Its clinical success underscores the growing potential of DXd-based ADCs in precision oncology.

18. Telisotuzumab vedotin-tllv (Emrelis)

In May 2025. AbbVie announced that EMRELIS™ (telisotuzumab vedotin-tllv) has been granted accelerated approval by the U.S. FDA for the treatment of adult patients with locally advanced or metastatic, non-squamous NSCLC with high c-Met protein overexpression (OE) who have received a prior systemic therapy.

Structure

Telisotuzumab vedotin is a first-in-class ADC comprising

• • A humanized monoclonal antibody targeting c-Met, a receptor tyrosine kinase overexpressed in various solid tumors, including NSCLC

• • A cytotoxic payload of monomethyl auristatin E (MMAE), a microtubule inhibitor

• • A protease-cleavable linker facilitating the release of MMAE within tumor cells

Mechanism of Action

Upon binding to c-Met-expressing tumor cells, EMRELIS™ is internalized, and the linker is cleaved by lysosomal enzymes to release MMAE. MMAE disrupts microtubule polymerization, leading to cell cycle arrest and apoptosis. This targeted delivery aims to maximize tumor cell killing while minimizing systemic toxicity.

Clinical Development & Approvals

This approval to EMRELIS™ (telisotuzumab vedotin-tllv) is based on results from the Phase 2 LUMINOSITY trial (NCT03539536), which evaluated its efficacy and safety in patients with c-Met protein–overexpressing, EGFR wild-type, advanced or metastatic non-squamous non-small cell lung cancer (NSCLC) who had received prior systemic therapy.
Key findings from the LUMINOSITY study (high c-Met protein overexpression cohort, n=84):

• • Overall Response Rate (ORR): 35% (95% CI: 24, 46)
  

• • Median Duration of Response (DOR): 7.2 months (95% CI: 4.2, 12)
  

EMRELIS™ represents a significant advancement in the treatment of c-Met overexpressing NSCLC, offering a new therapeutic option for patients with limited alternatives.