Adcetris (Brentuximab Vedotin) is a targeted therapy for the treatment of certain types of lymphoma. Developed by Seattle Genetics and Takeda, this drug conforms to the technical principle of antibody-drug conjugate (ADC), combining the specificity of antibodies with the potency of chemotherapy drugs to form an efficient and precise treatment mechanism.

Antibody Drug Conjugate

ADC is a new type of targeted therapy drug that combines monoclonal antibodies with cytotoxic payload by chemical means. This combination allows antibodies to accurately deliver cytotoxic drugs to tumor cells with specific surface receptors, increase the concentration of drugs in tumor cells, reduce damage to healthy tissues, and enhance the efficacy of drugs. ADC usually consists of three parts: monoclonal antibodies, linkers, and payloads (usually cytotoxic drugs). Monoclonal antibodies are the "missiles" of ADCs, which can recognize and bind to specific receptors on the surface of tumor cells; linkers are bridges connecting antibodies and cytotoxic drugs, which must be able to remain stable during drug delivery and release drugs after reaching target cells; payloads are the "explosives" of ADCs. After ADC drugs bind to target cells, cytotoxic drugs will be released to kill tumor cells. ADC drugs have good targeting and selectivity, can reduce damage to healthy tissues, reduce drug side effects, and improve efficacy. They have shown great potential in cancer treatment and have been widely studied and applied in clinical treatment.

Hodgkin's Lymphoma

Hodgkin Lymphoma (HL) is a malignant tumor that originates from the lymphatic system and is characterized by the presence of Reed-Sternberg cells. This cancer most commonly occurs in youth and early adulthood, but it can occur at any age. Its symptoms usually include painless lymphadenopathy, fever, night sweats, and weight loss. Although Hodgkin lymphoma is relatively rare, it has become an important paradigm for research and treatment models due to its unique biological characteristics and high sensitivity to treatment. Treatments for Hodgkin lymphoma include radiotherapy, chemotherapy, and increasingly immunotherapy and targeted therapy in recent years. Among these emerging treatment options, Adcetris has shown significant efficacy and has received high recognition.

Fig. 1. Adcetris structure (Pharmaceuticals (Basel). 2020, 13(9): 245).

In various clinical trials, Adcetris has demonstrated significant efficacy. For example, in clinical trials for the treatment of relapsed or refractory Hodgkin lymphoma, the results showed that both the complete remission rate and the overall remission rate were significantly improved. In addition, it was observed that Adcetris combined with traditional chemotherapy regimens showed an improved complete remission rate in first-line patients. Overall, this targeted therapy not only improves treatment effectiveness but also reduces the wide range of side effects associated with traditional therapies.

Brentuximab Vedotin

Brentuximab vedotin (Adcetris) is an anti-CD30 monoclonal antibody connected to the microtubule disruptor MMAE (monomethyl auristatin E) through a protease-sensitive cleavable citrulline-valine dipeptide (Val-Cit). This linker remains stable in the blood circulation and releases MMAE after being taken up by cells expressing CD30. Adcetris is mainly used to treat Hodgkin's lymphoma (HL) and systemic anaplastic large cell lymphoma (sALCL). It is designed to target a cell surface protein called CD30, which is usually highly expressed in cancer cells of these malignancies mentioned above. In the clinical setting, most patients who receive this treatment are those who have relapsed after conventional therapies such as chemotherapy, radiation therapy, or autologous stem cell transplantation or have failed to respond to these standard treatments.

* MMAE related products:

As a representative drug of the second-generation ADC, Adcetris has more advantages than the first-generation ADC. The second-generation ADC uses human-mouse chimeric antibodies or humanized monoclonal antibodies instead of mouse monoclonal antibodies, which reduces immunogenicity and enhances tumor targeting. At this time, more cytotoxic small molecules have been discovered, which are more effective and more active as payloads of ADC, and the linkers used in the second-generation ADC are also more stable. In short, in terms of clinical efficacy and safety, the second-generation ADC is superior to the first generation.

Adcetris Indication

Since its initial approval in the United States in 2011, more than 55,000 patients in the United States and more than 140,000 patients worldwide have been treated with Adcetris. Currently, Adcetris is approved for seven indications in the United States:

• In combination with doxorubicin, vinblastine, and dacarbazine for the treatment of previously untreated adult patients with stage III/IV classical Hodgkin lymphoma (cHL) (2018).
• In combination with doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide for pediatric patients 2 years and older with untreated high-risk cHL (2022).
• As consolidation therapy after autologous hematopoietic stem cell transplantation (auto-HSCT) in adult patients with cHL at high risk of relapse or progression (2015).
• Adult patients with classical Hodgkin lymphoma who have failed autologous hematopoietic stem cell transplantation or who are not candidates for autologous hematopoietic stem cell transplantation and have failed at least two prior multi-agent chemotherapy regimens (2011).
• In combination with cyclophosphamide, doxorubicin, and prednisone for the treatment of adult patients with previously untreated systemic anaplastic large cell lymphoma (sALCL) or CD30-expressing peripheral T-cell lymphoma (PTCL), including angioimmunoblastic T-cell lymphoma and unspecified PTCL (2018).
• Adult patients with sALCL who have failed at least one prior multi-agent chemotherapy regimen (2011).
• Adult patients with primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis fungoides (MF) who have received prior systemic therapy (2017).

* Adcetris related products:

Adcetris Mechanism of Action

CD30 is lowly expressed or not expressed on the surface of normally activated T cells and B cells, but is often highly expressed on the surface of Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (sALCL) cells. These characteristics make CD30 an ideal target for the treatment of HL and sALCL. That is, it is highly expressed on the surface of target cells and lowly expressed in normal tissues. The differentiated expression also reduces off-target toxicity. Therefore, the mechanism of action of Adcetris is that the conjugate enters the systemic circulation with intravenous infusion, and through the targeting effect of brentuximab, it is enriched on the surface of HL and sALCL cells expressing CD30, and is internalized by antibody-mediated cellular endocytosis. At this time, the linker is hydrolyzed by intracellular proteases, releasing toxic drugs, and MMAE binds to cytoplasmic tubulin, inhibiting cell division and killing tumor cells. Each brentuximab carries an average of 4 MMAE molecules, with a drug-antibody ratio (DAR) of 4 and a molecular weight of approximately 153 kDa.

Adcetris Clinical Trials

In 2011, the FDA approved Adcetris based on the following two clinical trial studies. In an open single-arm multicenter clinical trial, the efficacy of Adcetris in patients with relapsed HL after autologous stem cell transplantation was evaluated. A total of 102 patients were included in the study, and the primary endpoints were the objective response rate (ORR) and duration of response. The results showed that the ORR of the treated patients was 73%, and the median duration of response was 6.7 months.

Fig. 2. HL clinical results (Sourcing: FDA).

In another open single-arm multicenter clinical phase II trial, 58 patients were included to evaluate the efficacy of Adcetris in patients with recurrent sALCL. The primary endpoints of the trial were objective response rate and duration of response. The study showed that the ORR of the treated patients was 86%, and the median duration of response was 12.6 months.

Fig. 3. sALCL clinical results (Sourcing: FDA).

The most common adverse reactions (≥20%) include neutropenia, peripheral sensory neuropathy, fatigue, nausea, anemia, upper respiratory tract infection, diarrhea, fever, rash, thrombocytopenia, cough, vomiting, gastrointestinal discomfort, infusion reaction, etc. In 2021, Adcetris' global sales reached $1.732 billion. According to Clarivate's forecast, Adcetris sales will exceed $2 billion in 2024. Table 1 shows ADC sales in 2023.

Table. 1. Global sales of ADCs in 2023.