Antibody-drug conjugates (ADC) are novel cancer treatments that deliver the specificity of monoclonal antibodies and the cytotoxicity of small molecules. It's a unique combination that lets ADCs give cancer cells lethal doses of chemotherapy, but without damaging healthy tissue, and reduces the systemic toxicity of traditional chemotherapy. In recent decades, ADCs have evolved, from their first design to the next generation of products that are set to revolutionise cancer treatment.

Antibody Drug Conjugate Review

ADC is a therapeutic compound that combines monoclonal antibody-targeting capability with cytotoxic chemotherapeutic properties. After binding to the target antigen on the cancer cell surface, the entire complex is internalised by the cancer cell through endocytosis. In the cell, the linker is cleaved, which releases the cytotoxic drug that kills the cell, thereby exerting a lethal effect on the cancer cells. The specificity of the delivery also reduces collateral harm to healthy tissues, which is a big advantage over conventional chemotherapy. The basic building block of an ADC is made up of three components:

• Monoclonal Antibody: The targeting part, capable of recognizing and binding to specific antigens expressed on the surface of cancer cells.
• Cytotoxic Drug: The payload of the ADC, responsible for inducing cell death once inside the cancer cell.
• ADC Linker: A chemical group that connects the antibody to the cytotoxic drug, ensuring stability in circulation and controlled drug release in the tumor microenvironment.

Fig. 1. Antibody drug conjugate structure (Signal Transduct Target Ther. 2022, 7(1): 93).

BOC Sciences has strong R&D and manufacturing capabilities in the ADC field, committed to providing high-quality ADC products to meet the needs of pharmaceutical companies and research institutions. We offer comprehensive services from early discovery to clinical development stages, covering ADC design, synthesis, characterization, and process optimization. Our professional team is proficient in antibody-drug conjugation technology, providing various conjugation methods to ensure drug stability, targeting, and release efficacy. Additionally, BOC Sciences possesses advanced cGMP manufacturing capabilities, enabling large-scale production according to strict quality standards, ensuring high purity and consistency of the products.

ADC History

The concept of linking antibodies with cytotoxic drugs dates back to the early 20th century when Paul Ehrlich proposed the concept of the "magic bullet," a drug capable of selectively targeting and destroying cancer cells. However, it wasn't until the 1970s, with the advent of monoclonal antibody technology, that the development of ADCs became possible. Early research focused on directly attaching chemotherapy drugs to antibodies, but these initial constructs faced numerous challenges, including poor stability, low drug release efficiency, and limited therapeutic efficacy. Despite these setbacks, the potential of ADCs as targeted cancer therapies remained highly attractive. Over the years, significant advances in antibody engineering, linker chemistry, and cytotoxic drug development have gradually overcome many of the initial barriers, progressing from the early exploratory stages to clinical breakthroughs and the current era of second- and third-generation innovations.

Fig. 2. Antibody drug conjugate history (Signal Transduct Target Ther. 2022, 7(1): 93).

First Generation ADC

First-generation ADCs emerged in the late 1990s and early 2000s, driven by the success of monoclonal antibody technology and the demand for more effective cancer treatments. These early ADCs were characterized by their pioneering approach but were limited by certain technological constraints. First-generation ADCs used non-specific linkers and relatively less potent cytotoxic drugs. One of the earliest ADCs to enter clinical trials was Mylotarg, which targeted the CD33 antigen on leukemia cells. Mylotarg was formed by conjugating a humanized anti-CD33 antibody with the cytotoxic drug calicheamicin via a non-cleavable linker. While it showed some efficacy in treating acute myeloid leukemia (AML), its clinical application was limited by significant side effects and production challenges. The main drawbacks of first-generation ADCs included:

• Poor Stability: Non-cleavable linkers used in these ADCs often caused premature release of the cytotoxic drug in circulation, leading to systemic toxicity.
• Limited Targeting: The antibodies used in first-generation ADCs had limited affinity for the target antigen, leading to inefficient internalization of the ADC and low drug delivery efficacy.
• Low Drug-to-Antibody Ratio (DAR): The amount of cytotoxic drug carried by each ADC molecule was relatively low, reducing its overall potency.

Second Generation ADC

Building on the first generation, second-generation ADCs introduced significant improvements in linker chemistry, antibody design, and the selection of cytotoxic drugs. These advances were aimed at enhancing the stability, targeting efficiency, and therapeutic index of ADCs. One of the most successful second-generation ADCs is Kadcyla (T-DM1, ado-trastuzumab emtansine), which targets the HER2 receptor in breast cancer. Kadcyla links the anti-HER2 antibody trastuzumab with the cytotoxic drug DM1 via a cleavable linker. In clinical trials, Kadcyla demonstrated better efficacy and a safer profile compared to first-generation ADCs, and it has become the standard treatment for HER2-positive metastatic breast cancer. Second-generation ADCs marked significant progress in cancer therapy, with improvements in stability, targeting efficiency, and potency translating into better clinical outcomes for patients. However, these ADCs still face challenges, such as high production costs, complex manufacturing processes, and the need for further optimization of the DAR. Key innovations in second-generation ADCs include:

• Cleavable Linkers: These linkers remain stable in circulation but can release the cytotoxic drug after being internalized by cancer cells, significantly reducing systemic toxicity.
• Enhanced Antibody Affinity: Advanced antibody engineering techniques have made it possible to develop antibodies with higher affinity and specificity for the target antigen.
• More Potent Cytotoxic Drugs: Second-generation ADCs utilize more potent cytotoxic drugs, such as emtansine and monomethyl auristatin, enhancing the overall efficacy of the ADC.

Third Generation ADC

Third-generation ADCs represent the latest advancements in the ADC field. These ADCs incorporate more sophisticated technologies and innovative approaches to overcome the remaining limitations of previous generations. Several third-generation ADCs are currently in various stages of clinical development. A notable example is Enhertu (T-DXd, fam-trastuzumab deruxtecan), which targets HER2 in breast and gastric cancers. Enhertu uses a novel linker and more potent cytotoxic drug, showing impressive efficacy in clinical trials, even in patients with previously treatment-resistant cancers. Third-generation ADCs have the following cutting-edge features:

• Advanced Linker Chemistry: New linkers have been developed that provide better stability, controllable drug release, and reduced immunogenicity.
• Next-Generation Cytotoxic Drugs: Third-generation ADCs incorporate more potent, novel cytotoxic drugs, such as pyrrolo[2,3-d]pyrimidine benzotriazole (PBD) and duocarmycin.
• Multi-Targeting Strategies: Some third-generation ADCs are designed to simultaneously target multiple antigens, enhancing their ability to target a broader range of cancer cells.

ADC Innovation

With the rapid advancement of biotechnology and a deeper understanding of disease mechanisms, ADCs are undergoing a series of technological innovations that are expected to further enhance their efficacy, safety, and applicability, providing more powerful tools for future cancer treatments and other disease therapies.

• Antibody Innovation

The antibody component of next-generation ADCs is evolving from mouse-derived antibodies and minimally modified antibodies to fully human antibodies and highly modified antibodies. Fully human antibodies can significantly reduce immunogenicity and minimize immune-related adverse reactions, thereby improving drug safety and tolerability. Additionally, advancements in antibody engineering technologies, such as phage display and single B-cell technology, have further optimized antibody affinity and specificity. These technologies not only enhance the antibody's ability to recognize its target but also open up possibilities for developing ADCs targeting a range of diseases, including rare and autoimmune diseases.

• Linker Optimization

The linker is a crucial component of ADCs, and its stability directly impacts the drug's efficacy and safety. Next-generation ADC linkers are evolving from low-stability to high-stability, water-soluble linkers. For example, novel chemical linkers such as cyclobutane-1,1-dimide (cBu) and 1,2,4-trioxolane (TRX) frameworks can improve tumor delivery efficiency. Additionally, light-responsive cleavable and bioorthogonal cleavable technologies provide opportunities for the use of non-internalized antibodies. These techniques control drug release through external stimuli (such as light or specific chemical environments), further enhancing the precision of ADCs.

• Cytotoxic Drug

Next-generation ADC cytotoxic drugs are evolving from low-toxicity to high-toxicity, innovative mechanism-based toxins. For example, targeted protein degradation technologies such as PROTACs and molecular glues are expected to address the "undruggable" target issue. This technology works by marking the target protein for degradation, using the cell's protein degradation mechanisms to achieve therapeutic effects. Furthermore, the design of dual payload ADCs provides more options for ADC development. These innovations not only enhance the killing ability of ADCs but also reduce the risk of resistance.

• Conjugation Technology

Next-generation ADCs have made significant progress in conjugation technologies. For example, GlycoLink technology developed by GlycoBiotech uses the glycosylation sites on the antibody Fc region for targeted conjugation, improving ADC stability and uniformity while reducing off-target toxicity. Additionally, Pfizer's novel one-step conjugation technology achieves site-specific conjugation through engineered cysteine residues and mild reducing agents, avoiding the disulfide bond mismatch issue in traditional methods. These innovative technologies not only improve the efficacy and safety of ADCs but also accelerate the drug development process, driving the continuous development of the ADC field.

• New Targets and Indications

Innovation in ADC targets is a hot direction in current drug research and development. In recent years, ADC targets have gradually expanded from traditional popular targets such as HER2 and TROP2 to more innovative areas. For example, DLL3, a ligand of the Notch signaling pathway, is highly expressed in neuroendocrine tumors such as small-cell lung cancer, making it a highly promising target. Additionally, the B7-H3 target has shown good efficacy in small-cell lung cancer treatment, and its ADC drug HS-20093 has received FDA breakthrough therapy designation. The Claudin 18.2 target has also made breakthroughs in gastric cancer treatment, with clinical studies of CMG901 showing significant efficacy and safety. The development of these innovative targets not only enriches the therapeutic range of ADC drugs but also provides more precise options for cancer treatment.

Emerging Technologies in ADC

In recent years, ADC technology has made significant progress in the field of cancer treatment, with new technological directions constantly emerging. These innovations are driving the clinical application and enhancing the therapeutic effects of ADCs, including immunostimulatory antibody conjugates (ISACs), protein degrader-antibody conjugates (DACs), and bispecific antibody ADCs (BsADCs).

• Immunostimulatory Antibody Conjugates (ISACs)

Immunostimulatory antibody conjugates (ISACs) are a novel class of ADCs that combine immune stimulators with tumor-targeting antibodies to activate the immune system in the tumor microenvironment, enhancing anti-tumor effects. The mechanism of ISACs involves the specific delivery of immune agonists to the tumor site, activating antigen-presenting cells (APCs) and other immune cells to trigger an immune response and generate immune memory. For example, BDC-1001, a HER2-targeting ISAC conjugated with TLR7/8 agonists, has shown good tolerability and some anti-tumor activity in clinical trials. However, the development of ISACs still faces challenges such as potential immune toxicity and optimizing immune activation.

• Protein Degrader-Antibody Conjugates (DACs)

Protein degrader-antibody conjugates (DACs) combine the advantages of PROTAC technology and antibody-drug conjugates by linking protein degraders with monoclonal antibodies to specifically degrade target proteins. The design concept of DACs is to utilize cellular protein degradation mechanisms to mark the target protein for degradation, addressing the issue of "undruggable" targets that traditional small molecule inhibitors struggle to target. Compared to PROTACs, DACs can improve the pharmacokinetic properties of drugs and reduce off-target toxicity through the targeting ability of antibodies. For example, ORM-5029, a HER2/HER3-targeting DAC, is currently undergoing clinical trials. DAC development is still in its early stages, but it has shown significant in vitro and in vivo activity.

• Bispecific Antibody ADCs (BsADCs)

Bispecific antibody ADCs (BsADCs) are an innovative form of drug that combines bispecific antibodies with ADC technology, enabling the simultaneous targeting of two antigens, enhancing specificity and cytotoxicity toward tumor cells. This design not only improves the drug's targeting ability but may also overcome resistance through multiple mechanisms. Compared to traditional ADCs, BsADCs' unique dual epitopes/targets binding pattern allows them to bind antigens co-expressed in solid tumors to enhance selectivity and significantly improve internalization. These unique advantages make BsADCs a key force in next-generation ADCs. Currently, more than 10 BsADCs are undergoing clinical trials.

ADC Combination Therapy

The ADC combination therapy strategy is a treatment model that enhances anti-tumor effects through the synergistic action of multiple drugs. Its core mechanisms include four aspects: First, increasing the delivery of ADCs to tumor tissues, such as by using anti-angiogenic drugs to normalize tumor vasculature, thereby enhancing the cytotoxicity of ADCs. Second, regulating the expression of antibody target proteins, increasing the expression of tumor cell surface target antigens, promoting antibody-antigen binding, and enhancing ADC uptake and effective payload release. Third, enhancing payload activity through complementary mechanisms with other drugs or synergistic cytotoxic effects. Fourth, promoting anti-tumor immunity by utilizing immunotherapy to enhance antibody-dependent cytotoxicity or cell-mediated tumor recognition. Currently, ADC combination therapy has made significant progress in tumor fields such as breast cancer and lung cancer. For example, the objective response rate of T-DM1 combined with taxane drugs reaches 47.8%, with a median progression-free survival of 7.4 months. Additionally, combining ADCs with immune checkpoint inhibitors shows promising prospects, such as the combination of TROP2 ADCs with PD-1 inhibitors, where the objective response rate (ORR) can reach 87%. This combination strategy not only overcomes the resistance issues associated with single ADC treatments but also maximizes anti-tumor efficacy.

Future Outlook

The continuous innovation of next-generation antibody-drug conjugates is driving the development of this field. From optimizing antibodies and improving linkers to innovating cytotoxic drugs and breakthroughs in conjugation technologies, these technological advancements provide a solid foundation for the future development of ADC drugs. With ongoing progress in technology, ADCs are expected to play a more significant role in cancer and other disease treatments, offering more hope for patients.

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