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ADC Payload’s Target Landscape

Biointron 2025-01-17 Read time: 4 mins
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Structure of antibody–drug conjugates that have reach clinical trials and their payloads. DOI: 10.1186/s13045-022-01397-y

Antibody-drug conjugates (ADCs) combine the selectivity of monoclonal antibodies with the potency of cytotoxic agents, enabling the precise delivery of therapeutic payloads to cancer cells. Payloads play a critical role in determining the efficacy and therapeutic index of ADCs, as they induce cancer cell death while minimizing damage to healthy tissues. Historically, ADCs relied on microtubule inhibitors and DNA-alkylating agents. However, recent advancements, including the approval of trastuzumab deruxtecan (Enhertu) and sacituzumab govitecan (Trodelvy), have highlighted the potential of payload diversification for next-generation ADCs.

Key Components of ADC Payloads:

  1. Cytotoxic Potency: Payloads must maintain high potency even when only a small fraction reaches tumor cells. Many approved ADCs use payloads with sub-nanomolar IC50 values to compensate for delivery challenges.

  2. Target-Specific Action: The choice of payload should align with the antigen expression of the targeted cancer cells, ensuring minimal off-target effects.

  3. Therapeutic Index Optimization: Balancing payload potency with reduced systemic toxicity remains a key goal for ADC design.

Expanding the Payload Landscape

Topoisomerase 1 Inhibitors

The recent approvals of topoisomerase 1 (TOPO-1) inhibitor-based ADCs, such as trastuzumab deruxtecan and sacituzumab govitecan, represent a breakthrough in payload selection. These ADCs rely on high drug-to-antibody ratios (DARs), often as high as eight, to enhance payload delivery efficiency. These advancements have expanded ADC applications to tumors with both high and low antigen expression, as demonstrated by the approval of Enhertu in HER2-low breast cancers.

Emerging Payload Mechanisms:

1. Transcription Inhibitors:

Molecules like alpha-amanitin, derived from Amanita mushrooms, inhibit RNA polymerase II and show promise as payloads. Amanitin-based ADCs demonstrate high specificity, low efflux pump sensitivity, and the potential for immunogenic cell death. HDP-101, a BCMA-targeting amanitin ADC, has entered clinical trials for multiple myeloma.

2. Bcl-xL Inhibitors:

Targeting anti-apoptotic proteins like Bcl-xL offers a novel mechanism of action. For instance, ABBV-155, an anti-B7-H3 ADC conjugated with the Bcl-xL inhibitor clezutoclax, has demonstrated favorable safety profiles and clinical activity in solid tumors.

3. Immune-Stimulating Payloads:

ADCs conjugated with immune-activating agents, such as TLR7/8 agonists or STING agonists, aim to stimulate the innate immune system. BDC-1001, a HER2-targeting ADC conjugated to a TLR7/8 agonist, is in clinical trials and has shown durable antitumor responses and minimal toxicity.

Related: Antibody-Drug Conjugates: Transforming the Biopharma Landscape

Clinical and Preclinical Progress

Several unconventional payloads are under clinical and preclinical investigation:

  • RNA Polymerase Inhibitors: Amanitin derivatives have shown strong preclinical activity. HDP-101 is currently being tested for multiple myeloma, with promising early results.

  • Topoisomerase 2 Inhibitors: Despite early failures with doxorubicin-based ADCs, more potent derivatives like PNU-159682 are under evaluation, showing potential in solid tumors and hematologic malignancies.

  • Immune-Stimulating Payloads: Preclinical studies of TLR agonists and STING agonists have demonstrated strong antitumor activity and synergy with checkpoint inhibitors.

Future Directions in Payload Engineering

The evolution of ADC payloads reflects an ongoing effort to overcome challenges in delivery efficiency, toxicity, and resistance. New conjugation strategies, such as enzyme-assisted ligation and glycan-based technologies, are expected to further enhance payload stability and homogeneity. Additionally, the integration of ADCs with combination therapies, such as checkpoint inhibitors, opens new possibilities for addressing resistant tumors.

Related: Antibody-Drug Conjugates: Microtubule Inhibitors, DNA Binders, and Topoisomerase Inhibitors

Biointron provides antibody-drug conjugate products for in vivo research at Abinvivo, where we have a wide range of Benchmark Positive Antibodies, Isotype Negative Antibodies, Anti-Mouse Antibodies, Bispecific Antibodies, and Antibody-Drug Conjugates. Contact us to find out more at info@biointron.com or +86 400-828-8830 / +1(732)790-8340.


References:

  1. Conilh, L., Sadilkova, L., Viricel, W., & Dumontet, C. (2023). Payload diversification: a key step in the development of antibody–drug conjugates. Journal of Hematology & Oncology, 16(1). https://doi.org/10.1186/s13045-022-01397-y

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