ADCs, SMDCs and DACs for Cancer Treatment

In recent years, researchers have successfully developed and explored antibody-drug conjugates (ADCs), small molecule-drug conjugates (SMDCs), and degrader-antibody conjugates (DAC) to enhance chemotherapy drug delivery. These conjugated drugs enable targeted delivery and improve toxin therapeutic efficacy. What are their similarities, differences, respective advantages, current development status, and prospects?

drug-conjugates

Figure 1. Drug conjugates, source: reference [5]

Antibody-Drug Conjugates (ADCs): ADCs are complex molecules comprising an antibody linked to a biologically active cytotoxic (anticancer) payload or drug. These innovative compounds harness the targeting properties of monoclonal antibodies (mAbs) and the cancer-killing capabilities of cytotoxic drugs, aiming to distinguish between healthy and diseased tissue with remarkable specificity.

Small Molecule-Drug Conjugates (SMDCs): SMDCs represent a promising approach for targeted therapy, leveraging small molecules as targeted ligands to selectively release potent cytotoxic agents within the tumor microenvironment. This approach enhances the therapeutic potential of anticancer drugs by precisely targeting malignant cells while minimizing systemic toxicity.

Degrader-Antibody Conjugates (DACs): DACs are novel entities that merge a proteolysis-targeting chimera (PROTAC) payload with a monoclonal antibody through a chemical linker. This emerging therapeutic modality offers the potential for heightened efficacy and improved safety compared to either technology in isolation. By leveraging the precision of monoclonal antibodies and the cell-destroying capabilities of PROTAC payloads, DACs hold promise for targeted degradation of disease-causing proteins while sparing healthy tissues.

Each of these conjugated drug platforms represents a significant advancement in the field of targeted cancer therapy, with distinct mechanisms of action and potential advantages. However, further research and development efforts are needed to fully realize their clinical potential.

Mechanism of Action of ADCs, SMDCs, and DACs

Mechanism of Action of ADC: The primary antitumor action of ADCs is via targeting of the cytotoxic payload to the tumor cells. On binding of the mAb to the target antigen, the ADC is internalized into the tumor cell. The eventual linker breakdown promotes the intracellular release of the payload, where it exerts its microtubule- or DNA-damaging effects.

ADC-mechanism

Figure 2. Mechanism of Action of ADCs, source: reference [1]

Mechanism of Action of SMDC: SMDCs are designed to target specific cellular pathways or structures within cancer cells. They can penetrate cell membranes more easily than antibodies and deliver cytotoxic drugs directly to intracellular targets, leading to cell death.

SMDC-mechanism

Figure 3. SMDC mechanism of action, source: reference [5]

Mechanism of Action of DACs: DACs selectively recognize and bind to specific cell surface proteins using antibodies. Once bound, they facilitate the internalization of the target protein into the cell. Subsequently, DACs employ coupled degradation agents to trigger intracellular protein degradation mechanisms, marking the target protein for breakdown by the proteasome. This process ultimately leads to the degradation of the target proteins, offering a precise and targeted approach for therapeutic intervention.

DAC-MECHANISM

Figure 4. Mechanism of Action of DACs, source: reference [3]

Advantages of ADCs, SMDCs, and DACs

ADCs, SMDCs, and DACs all share common advantages in enhancing drug targeting, reducing side effects, and treating refractory diseases. Additionally, each type of conjugate has its unique advantages, enabling them to play crucial roles across diverse therapeutic contexts.

ADC's unique advantages

a. High specificity: The highly specific antibody component enables ADC to precisely target specific cell surface antigens.
b. High drug payload: ADC can carry high doses of drugs, enhancing therapeutic efficacy.
c. Broad applicability: ADC is widely used in cancer treatment, with multiple ADC drugs already on the market or in development.

SMDC's unique advantages

a. Cellular penetration: SMDC's small molecule properties allow it to penetrate cells more easily and target intracellular pathways.
b. Cost-effectiveness: Compared to ADCs and DACs, SMDCs typically have lower production costs and are easier to produce on a large scale.

DAC's unique advantages

a. Novel mechanism: DAC functions by degrading target proteins, presenting a novel therapeutic strategy distinct from traditional drug mechanisms.
b. Resistance avoidance: Treating diseases by degrading target proteins may help avoid resistance issues associated with certain drugs.
c. Wide applicability: Theoretically, DAC can target a wide range of different protein targets, making it suitable for various potential applications.

Clinical R&D of ADCs, SMDCs, and DACs

As of now, ADCs, SMDCs, and DACs have each achieved specific results in clinical research.

Approved ADCs and In Clinical Trials

ADCs are the most widely used clinically among these three types of drugs, with multiple ADCs already approved for the treatment of various types of cancer.

To date, a total of twelve ADCs have been approved by the FDA, including ado-trastuzumab emtansine (Kadcyla™), brentuximab vedotin (Adcetris™), inotuzumab ozogamicin (Besponsa™), gemtuzumab ozogamicin (Mylotarg™) , Moxetumomab pasudotox (Lumoxiti™), polatuzumab vedotin-piiq (Polivy™), Enfortumab vedotin (Padcev™), Sacituzumab govitecan (Trodelvy), Trastuzumab deruxtecan (Enhertu™), belantamab mafodotin-blmf (Blenrep™, withdrawn from FDA on November 22, 2022) , loncastuximab tesirine-lpyl (ZYNLONTA™), tisotumab vedotin-tftv (Tivdak) and mirvetuximab soravtansine (ELAHERE™).

approved-ADCs

Figure 5. Approved ADCs by FDA

In the 26 years since the first ADC clinical trial in 1997, 266 additional ADCs have been tested in over 1200 clinical trials.

Clinically-Tested-ADCs

Figure 6. Clinically Tested ADCs. doi: 10.1080/19420862.2023.2229101.

SMDCs In Clinical Trials

Research on SMDCs is relatively new, but they have already shown potential in certain areas of cancer treatment. Some SMDC products have entered the clinical trial stage, primarily focusing on the treatment of specific types of solid tumors and blood cancers. Specific examples of drugs are limited, with most still in the early or Phase 1 clinical trial stages.

While research on SMDCs is relatively new, they have shown promising potential in specific areas of cancer treatment. Several SMDCs have progressed to clinical trials, particularly targeting specific types of solid tumors and blood cancers. However, specific drug examples are limited, with the majority still in early or Phase 1 clinical trial stages.

VIP236

VIP236, developed by Vincerx Pharma, is considered a pioneering SMDC drug. VIP236 features a unique design aimed at effectively treating patients with invasive and metastatic cancers. It targets activated αvβ3 integrin, specifically homing to tumor sites and efficiently cleaving in the tumor microenvironment via neutrophil elastase (NE). In preclinical studies, VIP236 demonstrated significant anti-tumor activity in mouse models with various tumor types derived from patients. Moreover, VIP236 has shown potential to penetrate the blood-brain barrier, reducing the potential for brain metastasis. Currently, VIP236 is undergoing Phase 1 human clinical dose escalation trials, primarily focusing on patients with advanced solid tumors. Early safety assessments and clinical activity of this drug have shown promising results. Vincerx Pharma anticipates releasing preliminary clinical trial data in early 2024.

Enitociclib

Enitociclib, another drug from Vincerx Pharma, is also in Phase 1 clinical trials. This is a highly selective CDK9 inhibitor used in combination with Venetoclax and Prednisone for the treatment of lymphoma. The drug has shown evidence of therapeutic efficacy in patients with hematologic malignancies and solid tumors in early clinical studies.

DACs In Clinical Trials

Currently, DAC development globally is still in its early stages, and there is no consensus on the actual performance of DACs.

DAC-clinical

Figure 7. DACs in Clinical Trials（Nature Biotechnology, 40, 12–16 , 2022）

Conclusion

ADCs, SMDCs, and DACs hold a bright future in the pharmaceutical field. They exhibit tremendous potential in treating various diseases, especially cancer, each with its unique advantages. With continuous advancements in synthesis, conjugation, targeting, and structural optimization technologies, their efficacy and safety will further improve, and their development and application will become more widespread and precise.

References:
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2.Tarantino P, Ricciuti B, Pradhan SM, Tolaney SM. Optimizing the safety of antibody-drug conjugates for patients with solid tumours. Nat Rev Clin Oncol. 2023 Aug;20(8):558-576. doi: 10.1038/s41571-023-00783-w. Epub 2023 Jun 9. PMID: 37296177.
3.Hong KB, An H. Degrader-Antibody Conjugates: Emerging New Modality. J Med Chem. 2023 Jan 12;66(1):140-148. doi: 10.1021/acs.jmedchem.2c01791. Epub 2022 Dec 29. PMID: 36580273.
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5.Zhuang C, Guan X, Ma H, Cong H, Zhang W, Miao Z. Small molecule-drug conjugates: A novel strategy for cancer-targeted treatment. Eur J Med Chem. 2019 Feb 1;163:883-895. doi: 10.1016/j.ejmech.2018.12.035. Epub 2018 Dec 16. PMID: 30580240.