The immune system is the body's most vital defense system, protecting against pathogens and maintaining overall health. Leveraging the immune system's functions to treat diseases is the foundation of immunotherapy. Examples of immunotherapy include the development of antiviral vaccines and the cultivation of antibodies for viruses like HPV and HSV. Among these, antibody-drug conjugates (ADCs) have shown significant effectiveness in treating various cancers due to their precise targeting and powerful cytotoxic effects.

What is Immunotherapy?

Immunotherapy refers to treatments that work by inducing, enhancing, or suppressing immune responses. Therapies designed to trigger or amplify immune responses are known as activation immunotherapies, whereas those that reduce or inhibit immune responses are suppression immunotherapies. Simply put, the immune system helps protect against diseases and ailments, including cancer, through various organs and cells. Some immunotherapy drugs help the immune system work harder to locate and inhibit the growth and spread of cancer cells. Others modify immune function to better attack cancer cells. For some cancer patients, immunotherapy alone may be sufficient, while it can also serve as an adjunct to treatments like chemotherapy, radiation, or surgery.

Fig. 1. Immunotherapy types (Cancers (Basel). 2023, 15(10): 2721).

Immunotherapy vs Chemotherapy

Both immunotherapy and chemotherapy are effective cancer treatments, yet they differ in mechanisms and effects:

• Mechanism of Action: Chemotherapy uses chemicals to directly kill rapidly dividing cancer cells, having a cytotoxic effect. Immunotherapy, on the other hand, activates or modulates the immune system to more effectively identify and attack cancer cells, indirectly eliminating them by boosting the body's own immune response.
• Target Specificity: Chemotherapy drugs are generally non-specific, affecting not only cancer cells but also normal cells (especially rapidly dividing ones), causing side effects like hair loss and gastrointestinal discomfort. Immunotherapy, particularly targeted therapies like monoclonal antibodies and ADCs, often has higher specificity, focusing on tumor cells and sparing normal cells from harm.
• Drug Resistance: Resistance to chemotherapy drugs is common, as some patients may cease to respond after a period of treatment. Immunotherapy tends to have fewer resistance issues, especially with adoptive cell therapy or checkpoint inhibitors, which maintain the immune system's anticancer abilities for longer.
• Side Effects: Chemotherapy often has severe side effects, such as hair loss, nausea, and bone marrow suppression. Immunotherapy's side effects are generally linked to immune system overactivity, potentially leading to autoimmune responses, but overall tend to have a relatively lower impact on quality of life.
• Durability: Immunotherapy can establish long-lasting immune memory, allowing the body to continue monitoring and eliminating cancer cells after treatment, reducing the risk of relapse. Chemotherapy usually requires sustained treatment to maintain efficacy, with a higher relapse risk.

Immunotherapy for Cancer

Cancer immunotherapy is an innovative approach that utilizes the body's immune system to combat diseases. Unlike traditional treatments that directly kill tumor cells, immunotherapy enhances or modulates the immune system to more effectively recognize and attack cancer cells and pathogens. This method has shown remarkable results in cancer treatment and holds potential for treating infectious and autoimmune diseases as well. Mechanistically, cancer cells express unique markers called tumor antigens, which the immune system can recognize. However, cancer cells often evade immune attack due to various factors. Tumor immunotherapy aims to overcome these obstacles, reactivating the immune system's response to target cancer cells. Cancer immunotherapy can be categorized as follows:

• Active Immunotherapy: This involves tumor vaccines, such as cell-based, peptide, DC (dendritic cell), anti-idiotype antibody, and DNA vaccines. Most are still under development, although a few have reached the market.
• Passive Immunotherapy or Adoptive Immunotherapy: Involves transferring immune-active agents or cells with antitumor activity to patients, such as LAK and TIL cell therapies.
• Non-Specific Immunomodulatory Therapy: This encompasses a wide range, including well-known cytokines like interleukin and interferon therapies, as well as various immune-modulating drugs and plant extracts. The most prominent category currently is immune checkpoint inhibitor therapy, including CTLA-4 and PD-1/PD-L1 inhibitors. These inhibitors help counteract immune suppression by tumors, thereby reactivating antitumor immunity. Numerous drugs in this category, such as pembrolizumab, nivolumab, atezolizumab, durvalumab, camrelizumab, and sintilimab, have been approved for use.

Types of Immunotherapy

Each immunotherapy modality has a different mechanism and use case. Immunotherapies are generally of two kinds—checkpoint inhibitors, adoptive cell therapy, cancer vaccines, cytokine therapy and ADCs. They are fashioned according to layers or functions of the immune system and can be performed alone or in combination with another therapy (eg, chemotherapy or radiotherapy) for improved effectiveness. These main classes of immunotherapies are explained in detail below:

• Checkpoint Inhibitors

Checkpoint inhibitors are treatments that silence immune checkpoint molecules so the immune system can recognise and kill cancer cells. Immune checkpoints regulate immune action, and are the means by which the immune system rebounds from the attack on the body's own cells. Yet cancer cells usually dodge immune attack by over-expressing checkpoint proteins such as PDL1 or CTLA-4, which dampen immune cell activity. Blockers of these checkpoint pathways (PD-1/PD-L1 inhibitors, CTLA-4 inhibitors) relieve the immune system's muzzle and allow T cells to activate again and strike cancer cells. Most influential treatments such as pembrolizumab (Keytruda) and nivolumab (Opdivo) have been effective in multiple cancers. Checkpoint inhibitors are the new cancer treatment approach that promises robust immune responses in most patients.

• Adoptive Cell Therapy

The method is adoptive cell therapy (ACT), where patients' immune cells are 'engineered' out of the body to have an even stronger anti-cancer effect. Most commonly, immune cells such as T cells or natural killer (NK) cells are removed from the patient, genetically altered or enriched in the lab, and infused back to boost the body's immune response to cancer. A big sub-type of ACT is chimeric antigen receptor T cell (CAR-T) therapy. CAR-T treatments work by genetically engineering T cells to express antigen receptors that identify and attack cancer cells. It has been shown to be highly effective in hematological cancers like acute lymphoblastic leukemia and non-Hodgkin lymphoma, which is one of the most radical breakthroughs in immunotherapy. Now, thanks to technological advancements, adoptive cell therapy has now been applied to solid tumours.

• Cancer Vaccines

Cancer vaccines utilize cancer-associated antigens to activate the patient's immune system to specifically recognize and attack tumor cells. Unlike preventive vaccines for infections, cancer vaccines are usually therapeutic, aiming to help patients clear tumor cells. Cancer vaccines can be classified into types such as autologous vaccines, allogeneic vaccines, and peptide vaccines. Autologous vaccines use the patient's own tumor cells as an antigen source, while allogeneic vaccines use tumor cells or known cancer antigens from other patients. Recently, neoantigen-based vaccines, customized according to a patient's specific tumor mutations using advanced gene sequencing, have rapidly developed. These vaccines hold promise for treating difficult-to-treat cancers like pancreatic, lung, and melanoma.

• Cytokine Therapy

Cytokine therapy involves the direct injection of immune-regulating molecules, such as interleukin-2 and interferons, to enhance the patient's immune response against tumors. Cytokines act as "messengers" in the immune system, controlling the growth, differentiation, and activation of immune cells. For instance, interleukin-2 (IL-2) can promote T cell proliferation, strengthening their anti-cancer capabilities, and has been used in certain cancers such as renal cell carcinoma and melanoma. Interferon (IFN-α) can improve the immune system's ability to recognize cancer cells, aiding in their elimination. While cytokine therapy is effective in specific cancer types, its significant side effects, which can trigger serious immune reactions, mean it is used cautiously in clinical settings and often combined with other treatments.

• Antibody-Drug Conjugate

ADCs are a precise treatment strategy that combines monoclonal antibodies with potent small-molecule drugs. ADC therapy leverages the targeting ability of antibodies to deliver chemotherapy drugs directly to tumor cells, reducing harm to normal cells. The core principle of ADCs lies in their targeting specificity: monoclonal antibodies can specifically recognize antigens on the tumor cell surface, delivering cytotoxic drugs directly inside tumor cells while sparing normal cells. For example, T-DM1 (Kadcyla), approved for breast cancer treatment, targets the HER2 receptor, linking the antibody trastuzumab with the cytotoxic drug DM1 to efficiently kill cancer cells while protecting healthy tissue. Due to its high targeting ability and potency, ADC therapy is considered an ideal combination of targeted therapy and chemotherapy, especially suitable for tumors with high resistance to traditional treatments.

Antibody Drug Conjugate Immunotherapy

An ADC is an emerging form of immunotherapy that combines the targeting specificity of antibodies with the cytotoxic power of small-molecule drugs, forming an efficient and precise anti-tumor strategy. ADCs typically consist of three components: a monoclonal antibody, a linker, and a small-molecule cytotoxic drug. Mechanistically, the antibody specifically recognizes certain antigens on the surface of tumor cells, enabling highly targeted therapy. The linker connects the antibody and drug, releasing the drug once inside the tumor cell in response to the cellular environment. Finally, the cytotoxic drug, released within the tumor cell, acts on the nucleus or microtubule structures to induce cell death. This targeted delivery not only improves therapeutic efficacy but also significantly reduces systemic side effects typical of conventional chemotherapy.

• Monoclonal Antibody: Monoclonal antibodies are designed to specifically recognize and bind to unique antigens on the surface of tumor cells, enabling precise targeting at the cellular level. Most antibodies used in ADCs are fully human or humanized to minimize immunogenic responses in patients.
• Linker: The linker connects the antibody and cytotoxic drug, and its stability is critical to the ADC's effectiveness. An ideal linker remains stable in the bloodstream but quickly cleaves within the tumor cell to release the drug. Linkers are classified into cleavable and non-cleavable types, depending on the design.
• Small-Molecule Drug: The ADC's cytotoxicity largely comes from the small-molecule drug it carries. These drugs are usually highly potent, capable of killing tumor cells at very low doses. Common cytotoxic drugs include microtubule inhibitors and DNA-damaging agents, such as MMAE and MMAF.

Fig. 2. General mechanism of ADCs to kill tumor cells (Trends in Analytical Chemistry. 2022, 152: 116621).

However, ADC therapy also faces several challenges. First, drug tolerance may arise, as tumor cells can develop resistance to ADC drugs over long-term treatment, impacting efficacy. Target specificity is also crucial—if the antibody's target selection is suboptimal, it could affect normal cells and cause side effects. Immunogenicity is another concern, as heterologous components in the antibody may trigger immune responses in patients, impacting the ADC's safety and efficacy. Additionally, controlling drug release is essential; improper linker control may cause premature release of the toxic drug in healthy tissues, leading to adverse reactions. Despite these challenges, advancements in ADC research and technology are gradually overcoming these issues, making ADC immunotherapy a promising targeted cancer treatment.

ADC Services from BOC Sciences

Based on this, BOC Sciences offers all the ADC research and production services right from the proof of concept to production at scale. Services offered: ADC molecule design and synthesis, linker/cytotoxic drug screening and modification, optimization of antibody modification and conjugation process. In conjunction with the advanced labs and experience, BOC Sciences can modify linker chemical composition according to the needs of the client for the goal of stable, rapid release and granular targeting. They also have cGMP-controlled production lines to service clinical and commercial uses from the lab scale up to industrial scale.

Antibody Drug Conjugate FDA Approved

ADCs have made significant clinical progress in recent years, with several ADC products receiving FDA approval for treating various cancers. FDA-approved ADCs combine the high specificity of antibodies with the potency of cytotoxic drugs to accurately target and destroy cancer cells. For example, trastuzumab emtansine (T-DM1, brand name Kadcyla) is approved for HER2-positive breast cancer treatment. It links the anti-HER2 antibody trastuzumab with the cytotoxic drug DM1, allowing the drug to target HER2-positive tumor cells specifically, thus reducing harm to healthy cells. Another example, brentuximab vedotin (brand name Adcetris), is used for Hodgkin's lymphoma and systemic anaplastic large cell lymphoma. This ADC combines an anti-CD30 antibody with the cytotoxin MMAE, achieving precise killing of CD30-positive cancer cells. These FDA-approved ADCs offer new therapeutic options for cancer patients, especially those resistant to traditional treatments, by utilizing a precise targeting mechanism and effective drug release. The development of ADCs marks a new chapter in precision oncology, with more ADCs expected to receive FDA approval as technology advances, further expanding their application in cancer treatment.

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