FDA-Approved Antibody-Drug Conjugates up to 2024

Antibody-drug conjugates (ADCs) are a class of highly targeted anticancer therapies that link specific antibodies to potent chemotherapeutic drugs to achieve targeted delivery and reduce systemic toxicity. As of 2024, the U.S. Food and Drug Administration (FDA) has approved a number of ADCs for the treatment of a variety of malignancies such as breast cancer, non-small cell lung cancer, and lymphoma. Each ADC locates cancer cells through its specific antibody and then releases its potent cytotoxic drug, causing cancer cell death. These approved ADCs include T-DM1 (Kadcyla), Brentuximab vedotin (Adcetris), and Enfortumab vedotin (Padcev). FDA's continued approval and advances in new technologies mark a bright future for ADCs in cancer treatment. However, these drugs still face challenges such as complex production and high costs, and researchers are working to optimize their efficacy and safety so that they can be more widely and affordably used in clinical treatment.

Antibody Drug Conjugate

ADCs use specific linkers to connect antibodies and small molecule cytotoxic drugs. Their main components include antibodies, linkers, and small molecule cytotoxic drugs. Antibody molecules mainly play a role in targeted delivery, while small molecule drugs play a role in exerting therapeutic effects. However, some antibodies also have anti-tumor pharmacodynamic effects. Compared with other chemotherapy drugs, ADC drugs greatly improve the specificity of drug administration through the specific binding of antigens and antibodies. Mechanistically, antibodies bind to specific antigens on the tumor cell membrane, induce endocytosis, and allow antibodies and cytotoxic small molecule drugs attached to them to enter the cell and then undergo lysosomal degradation. Small molecule drugs are released into cells and induce cell apoptosis through DNA insertion or inhibition of microtubule synthesis.

PEG for ADC Linker

Polyethylene glycol (PEG) has high water solubility and biocompatibility, which makes it an ideal linker material. ADC achieves targeted treatment of diseases by combining mAb with small molecules or peptides of payload drugs. However, there are differences in solubility and stability between monoclonal antibodies and small molecule drugs. PEG can build a "bridge" between these small molecule drugs and antibodies, improve their solubility, and greatly enhance the stability of the entire ADC molecule. In addition, the different lengths of PEG can precisely regulate the pharmacokinetic properties of ADC. By tailoring the length and structure of PEG, the overall morphology, size and charge of ADC can be improved, thereby optimizing its distribution and permeation properties in the body. This flexibility makes PEG a versatile tool for designing a variety of ADCs. Based on this, BOC Sciences offers a variety of functionalized PEG linkers of different molecular weights to support ADC research and development. Our representative PEG linkers include:

ADC Drug

Many ADCs have shown excellent activity against refractory cancers and have attracted worldwide attention. Although ADCs have brought great challenges to researchers, especially in identifying suitable combinations of antibodies, linkers, and payloads, 15 ADCs have been approved by the FDA. Among them, seven have also been approved by the European Medicines Agency (EMA). Specifically, they are Adcetris®, Kadcyla®, Besponsa®, Mylotarg®, Polivy®, Blenrep®, and Enhertu®. Among the 15 ADCs, there are two TDM-1 biosimilars, six for the treatment of hematological tumors (targets: BCMA, CD30, CD33, CD22, CD19, CD79b), and seven for the treatment of solid tumors (EGFR, HER-2, Nectin-4, TROP-2, TF).

Mylotarg

Mylotarg (gemtuzumab ozogamicin) from Pfizer/Wyeth is the first ADC to enter the market worldwide. It consists of a recombinant humanized anti-CD33 mAb (IgG4κ antibody hP67.6) covalently linked to a calicheamicin-derived payload (N-acetyl-γ-calicheamicin1,2-dimethyl hydrazine dichloride) via a pH-sensitive hydrazone linker, as shown in Fig. 1.

Fig. 1. Structure of Mylotarg.

Mylotarg received accelerated approval for relapsed CD33+ acute myeloid leukemia (AML) in 2000, but subsequent clinical trials failed to continue to demonstrate the efficacy of this new drug, and there were some concerns about its safety (fatal liver injury), so Pfizer took the initiative to withdraw it from the market. After adjusting the dose and supplementing more data, the benefit-risk ratio of this innovative drug was finally recognized. In 2017, it was re-listed and introduced into different patient populations. The maximum plasma concentration was reduced through dose adjustment, thereby improving the safety and response rate when administered as a single agent or in combination. Mylotarg's antitumor activity derives from a semisynthetic payload, a calicheamicin derivative (N-acetyl-γ-calicheamicin 1,2-dimethylhydrazine dichloride) produced by microbial fermentation followed by synthetic modification. The payload consists of four glycosidic units, a fully substituted iodobenzoate moiety, and an aglycon. The highly reactive hexen-3-ene-1,5-diyne subunit can readily trigger aromatization via a Bergmann cyclization reaction to generate a benzene-1,4-diazolyl radical. This aromatization process provides a dizolyl radical that can abstract two hydrogen atoms from the DNA backbone, leading to irreparable double-strand (ds) DNA breaks, followed by cell cycle arrest and apoptotic cell death.

Adcetris

Adcetris (brentuximab vedotin) from Seagen consists of a CD30-specific mAb coupled to MMAE. It was approved by the FDA in 2011, becoming the second ADC to enter the oncology market, see Fig. 2. In the United States, Europe, and Japan, the drug has been approved for Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (sALCL).

Fig. 2. Structure of Adcetris.

The anticancer activity of Adcetris is caused by MMAE binding to tubulin. This disrupts the intracellular microtubule network and subsequently induces cell cycle arrest and apoptotic cell death. In addition, likely due to the IgG1 antibody isotype, in vitro data provide evidence for ADCP antitumor activity. It is known from the first generation of ADCs that ~0.1% of the injected ADC reaches the target tumor site, so the potency of the cytotoxic drug and/or DAR needs to be increased to improve therapeutic activity. Adcetris addresses both requirements by adopting a more cytotoxic payload, MMAE (a tubulin-targeting agent), which belongs to the auristatin drug payload family (cytotoxicity in the low nanomolar to subnanomolar range). The second-generation ADC (Adcetris) addressed the defect of the acid-cleavable hydrazone linker in Mylotarg that led to premature drug release by using a protease-cleavable mc-vc-PABC-MMAE linker-drug combination. Compared with Mylotarg, which uses IgG4 antibody, the IgG subclass used in Adcetris is IgG1. This is the most common subclass of ADC, and although their serum half-life is similar to IgG4, they have higher complement fixation and FcγR binding efficiency.

Kadcyla

In 2013, Kadcyla (ado-trastuzumab emtansine), developed and marketed by Genentech/Roche, revolutionized the ADC space by becoming the first ADC approved for the treatment of solid tumors. The drug is indicated as adjuvant (postoperative) therapy for HER2+ early breast cancer, either alone or in combination, in patients who have previously received trastuzumab (Herceptin) and a taxane.

Fig. 3. Structure of Kadcyla.

Kadcyla comprises the humanized anti-HER2 IgG1 antibody trastuzumab linked to the antimitotic agent DM1, see Fig. 3. DM1 is a potent pentanediol derivative that belongs to the family of madonins natural products. While pentanediol is difficult to conjugate due to its lack of reactive functional groups, DM1 contains a thiopropionyl group instead of the native N-acetyl group, which allows lysine antibody conjugation via the non-reducible thioether linker maleimidocyclohexane-1-carboxylate (MCC). In contrast to the two FDA-approved ADCs mentioned above, Kadcyla consists of a non-cleavable thioether linker. Non-cleavable linkers tend to be more stable than their cleavable counterparts, but they rely on lysosomal degradation of the entire antibody-linker construct to release the payload. This often results in the retention of charged amino acids on the payload, which may affect its action or cell permeability. In human plasma, the Kadcyla catabolites, MCC-DM1, lysine-bound carnosine (Lys-MCC-DM1), and DM1 have been detected at low levels. The cytotoxic effects of Kadcyla are caused by the binding of DM1-containing catabolites (mainly Lys-MCC-DM1) to tubulin, which disrupts the microtubule network and induces cell cycle arrest and apoptotic cell death at subnanomolar concentrations. In addition, in vitro studies have shown that Kadcyla mediates ADCC.

Besponsa

Besponsa (inotuzmab ozogamicin (Pfizer/Wyeth)) was approved by the FDA in 2017 and targets CD22+ B-cell acute lymphoblastic leukemia (B-ALL). It is based on an ADC platform similar to Mylotarg (Fig. 4). The first difference is the monoclonal antibody, hence the antigen target and the cancer indication. The recombinant humanized monoclonal IgG4 antibody (G544) used in Besponsa is selective for CD22 expressed on B cells in all patients with mature B-ALL and >90% in patients with precursor B-ALL. In addition, preclinical studies have shown that Besponsa can be tolerated at a higher ~6 DAR without significant aggregation.

Fig. 4. Structure of Besponsa.

Polivy

Polivy is an anti-CD79b ADC developed by Genentech/Roche, using proprietary technology developed by Seagen. The drug was first approved by the FDA for accelerated marketing in 2019, in combination with bendamustine and rituximab, for the treatment of adult patients with at least two relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL). Subsequently, it was approved for marketing in the European Union and Japan in January and March 2021, respectively. Compared with traditional treatment options, Polivy can significantly improve patients' clinical outcomes and is the first new treatment option in 20 years to significantly improve relapsed or refractory diffuse large B-cell lymphoma.

Fig. 5. Structure of Polivy and Padcev.

The drug is coupled by an anti-CD79b monoclonal antibody, a protease-cleavable linker, and MMAE. CD79b is a B-cell-specific surface protein that is highly expressed in more than 90% of B-cell non-Hodgkin's lymphomas. After binding to the antibody, CD79b is rapidly internalized and delivered to the lysosome. Therefore, CD79b becomes an ideal target for the treatment of this type of lymphoma. Polivy has a drug/antibody ratio (DAR) of 3-4 and a molecular weight of approximately 150 kDa.

Padcev

Padcev, developed and produced by Astellas Pharma and Seagen, is a Nectin4-directed ADC. It was first granted accelerated approval in 2019 for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma who had previously received a programmed death receptor-1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitor, as well as platinum-containing therapy. In 2021, the indication was granted regular approval, and Padcev was granted accelerated approval for patients who were not eligible for cisplatin-containing chemotherapy and had previously received one or more lines of therapy.

Padcev consists of a human monoclonal antibody targeting Nectin-4, a protease-cleavable linker, and MMAE conjugated. Nectin-4 is a cell adhesion molecule that is expressed at low levels in healthy adult tissues but is highly expressed in a variety of tumor cells, such as in tissues such as urothelial carcinoma, bladder cancer, breast cancer, ovarian cancer, gastric cancer, hepatocellular carcinoma, and pancreatic cancer. Nectin-4 has a specific high expression and is closely related to the occurrence and metastasis of tumors. It can promote tumor cell proliferation, differentiation, migration, invasion, etc. by activating the PI3K/AKT pathway. Therefore, Nectin-4 has become an important target for the diagnosis and treatment of many solid tumors. Padcev is the first ADC approved for the treatment of urothelial carcinoma and the first approved drug targeting Nectin-4.

Lumoxiti

Lumoxiti (Moxetumomab pasudotox) 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, it induces apoptosis by catalyzing the ADP ribosylation of diphenyldiamine residues in elongation factor-2 (EF-2). Lumoxiti was approved by the FDA for marketing 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. But five months later, in July of the same year, the EMA issued an announcement revoking its marketing authorization in the European Union. However, due to very low clinical use, AstraZeneca permanently withdrew Lumoxiti from the US market in July 2023.

Enhertu

Enhertu (fam-trastuzumab deruxtecan-nxki), developed by Daichi Sankyo/AstraZeneca, received accelerated approval from the FDA in December 2019 for the treatment of adult patients with unresectable or metastatic HER2+ breast cancer who have received two or more prior anti-HER2+ treatment regimens. In 2020, the FDA approved it for the treatment of patients with metastatic HER2-mutated non-small cell lung cancer (NSCLC) following platinum therapy, and granted priority review for the treatment of HER2+ metastatic gastric or gastroesophageal junction adenocarcinoma. Demonstrating the continued promise of Enhertu, in 2021, the ADC was approved in the U.S. for a second oncology indication for adult patients with locally advanced or metastatic HER2+ gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based treatment regimen.

Fig. 6. Structure of Enhertu.

The ADC consists of an anti-HER2 antibody, a protease-cleavable tetrapeptide linker, and DXd as the drug payload. DXd is a novel exatecan derivative designed using Daiichi Sankyo's proprietary ADC technology. It belongs to the camptothecin class of drug payloads, which elicits its cytotoxic effects by inhibiting topoisomerase I (TOP1). TOP1 is essential in higher eukaryotes as it is responsible for relaxing DNA supercoils generated by transcription, replication, and chromatin remodeling. Therefore, inhibition of this enzyme results in DNA damage and apoptotic cell death, leading to the destruction of HER2+ tumor cells.

Trodelvy

In April 2020, Trodelvy received accelerated approval from the FDA for the treatment of patients with locally advanced or metastatic triple-negative breast cancer (mTNBC) who have received at least two prior therapies for metastatic disease. In 2021, Trodelvy was given accelerated approval for a second indication in patients with locally advanced or metastatic urothelial carcinoma who have previously received platinum-containing chemotherapy and a PD-1 or PD-L1 inhibitor.

Fig. 7. Structure of Trodelvy.

Trodelvy consists of a fully humanized hRS7 IgG1κ antibody targeting TROP2 conjugated to SN-38 via an acid-sensitive hydrolyzable linker called CL2A. This ADC is another example of an ADC with a high DAR, consisting of approximately 7.6 SN-38 molecules per antibody, which does not affect its binding and pharmacokinetics. In addition, because Trodelvy delivers SN-38 in its most active non-glucuronidated form, this may explain the improved toxicity profile, such as a lower frequency of severe diarrhea than that seen with irinotecan. PEGylation and the incorporation of lysine residues in the linker system are thought to reduce ADC aggregation.

Blenrep

GSK's ADC, Blenrep (belantamab mafodotin-blmf) is the first approved anti-BCMA (B-cell maturation antigen) therapy. In August 2020, it received accelerated approval from the FDA for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least 4 prior therapies, including anti-CD38 monoclonal antibodies, proteasome inhibitors, and immunomodulators. In addition to Kadcyla, this is currently the only FDA-approved ADC with a non-cleavable linker. To date, Blenrep is the only FDA-approved ADC with a fucosylated Fc-engineered antibody.

Fig. 8. Structure of Blenrep.

Blenrep consists of the antimitotic auristatin payload MMAF. While MMAF also prevents cell division by inhibiting tubulin polymerization, this substitution results in attenuated antitumor activity. MMAF has IC50 values in the 100-250 nM range, which is more than 100-fold higher than MMAE. While the low cell permeability of MMAF resulting from the charged phenylalanine residues limits its toxicity, MMAF-mediated killing is limited to target cells if the free drug is released prematurely from the ADC, thus not causing bystander killing. Therefore, MMAF ADCs require high tumor expression of the target antigen to be effective but are more effective than vc-MMAE ADCs at targeting internalized antigens in vitro.

Zynlonta

Zynlonta (loncastuximab tesirine-lpyl), developed by ADC Therapeutics, is a CD19-targeted ADC indicated for adult patients with relapsed or refractory large B-cell lymphoma, including diffuse large B-cell lymphoma (DLBCL), low-grade lymphoma not otherwise specified, and high-grade B-cell lymphoma, after two or more lines of systemic therapy. It received accelerated approval for medical use from the FDA in April 2021.

Fig. 9. Structure of Zynlonta.

Zynlonta consists of a humanized IgG1κ mAb conjugated to SG3199, a cytotoxic pyrrolobenzodiazepine (PBD) dimer alkylating agent, via a protease-cleavable valine-alanine linker. SG3199 exhibits cytotoxicity in the picomolar range against a variety of cancer cell types, meaning that Zynlonta has the most cytotoxic payload used to date in a marketed ADC. PBD dimers are extremely potent compounds that exert their cytotoxic effects by selectively alkylating the minor grooves of DNA, thereby forming adducts to inhibit nucleic acid synthesis. After insertion into the fine groove, the cathodic bond is formed by nucleophilic attack of guanine N2 at the electrophilic C11 position on the PBD.

Tivdak

In September 2021, the FDA granted accelerated approval to Tivdak (tisotumab vedotin-tftv). Tivdak, co-developed by Seagen and Genmab, is the first and only ADC approved for the treatment of adult patients with recurrent or metastatic cervical cancer whose disease has progressed during or after chemotherapy. This is the third ADC approved by the FDA for Seagen, further consolidating their dominance as an industry leader in ADC technology.

Fig. 10. Structure of Tivdak.

Tivdak is a tissue factor (TF)-directed ADC consisting of a human anti-TF IgG1κ antibody coupled to MMAE via the same protease-cleavable mc-vc-PABC linker construct as in Adcetris, Polivy, and Padcev. Tivdak carries an average of four MMAE molecules per monoclonal antibody. In addition, in vitro studies have shown that this ADC also mediates ADCP and ADCC effector functions, providing multi-mode anti-tumor activity.

Akalux

In September 2020, Akalux (cetuximab saratolacan) was approved in Japan, becoming the world's first approved photoimmunotherapy drug for head and neck cancer tumors. Akalux is composed of cetuximab (cetuximab) and IRDye700DX, which can target the epidermal growth factor receptor (EGFR). Akalux contains antibodies that attack cancer cells and chemicals that react to light, and is administered to patients by infusion. After the drug and cancer cells are combined, near-infrared light is irradiated to the patient to activate the antibodies in the drug and destroy the cancer cells. This treatment method is called photoimmunotherapy. The uniqueness of photoimmunotherapy lies in the use of antibody-mediated targeted delivery to achieve high tumor specificity, while using laser-activated biophysical mechanisms to accurately induce the rapid death of cancer cells and avoid harming surrounding normal tissues.

Aidixi

Aidixi (disitamab vedotin, RC48) is an antibody-drug conjugate targeting HER2 developed by Remegen. It consists of a new humanized anti-HER2 antibody with higher affinity, a cleavable linker and a microtubule inhibitor, MMAE. Its mechanism of action includes inhibition of the HER2 signaling pathway and the cytotoxicity of MMAE. In June 2021 and December 2021, Aidixi was approved for marketing by NMPA for the treatment of patients with HER2-overexpressing locally advanced or metastatic gastric cancer (including gastroesophageal junction adenocarcinoma) who have received at least two systemic chemotherapy regimens, as well as the treatment of 2+ or 3+ locally advanced or metastatic urothelial carcinoma.

Elahere

Elahere (mirvetuximab soravtansine-gynx) was approved by the FDA as a monotherapy in November 2022 for the treatment of adult patients with FRα-positive, platinum-resistant epithelial ovarian cancer, fallopian tube cancer, and primary peritoneal cancer who have previously received 1-3 systemic treatment regimens. Elahere is a FRα-targeted ADC composed of IgG1 subtype anti-FRα humanized monoclonal antibody M9346A, anti-tubulin agent DM4 (a maytansine derivative) and linker. FRɑ 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 addition to providing PEG products with a variety of specifications and molecular weights, BOC Sciences is also committed to providing high-quality PEGylation services. We support customers to customize PEG compounds with specific structures and functions. From the initial molecular design and synthesis to the later purification and analysis, we are committed to providing customers with efficient and reliable solutions. Especially for the PEGylation modification of ADC, we can significantly improve the pharmacokinetic and pharmacodynamic properties of ADC, reduce toxic side effects, and enhance clinical effects by optimizing the connection strategy. Our PEG compounds undergo strict quality control to ensure their stability and consistency, thereby improving the safety and efficacy of ADC drugs. If you need related PEG products or services, please contact us for more information.

Reference

1. Tong, J.T.W. et al. An Insight into FDA Approved Antibody-Drug Conjugates for Cancer Therapy. Molecules. 2021, 26(19): 5847.