Antibody-drug conjugates (ADCs) are transforming the landscape of targeted cancer therapies, but their reliance on microtubule and topoisomerase I inhibitors leaves room for resistance and relapse. Amanitin, a toxin derived from the infamous ‘death cap’ mushroom (Amanita phalloides), is now emerging as a novel payload for next-generation ADCs.[1][2]
By irreversibly inhibiting RNA Polymerase II, Amanitin-based ADCs, known as Antibody Targeted Amanitin Conjugates or ATACs, offer a fundamentally new mechanism of cytotoxicity, targeting both proliferative and dormant tumor cells and circumventing classic drug resistance. This article reviews the biology, engineering, preclinical data, and clinical promise of Amanitin ADCs, with a focus on the Heidelberg Pharma portfolio and the future direction of this innovative therapeutic strategy.
The evolution of ADCs has been marked by a focus on two principal payload classes: microtubule inhibitors (e.g., MMAE) and topoisomerase I inhibitors (e.g., DXd, SN-38). However, resistance mechanisms such as efflux pumps and the inability to eradicate dormant tumor cells continue to limit their long-term efficacy. Amanitin, a bicyclic octapeptide produced by Amanita mushrooms, is now being leveraged for its potent, unique inhibition of RNA Polymerase II, marking a possible paradigm shift in ADC payload design.
Amanitin: A Novel Mechanism of Action
Unlike traditional chemotherapeutics that disrupt DNA replication or cell division, Amanitin payloads bind to RNA Polymerase II with high specificity and irreversibility, halting mRNA transcription and, consequently, all protein synthesis. This leads to inevitable apoptosis, regardless of the cell’s proliferation status. As a result, Amanitin-based ADCs can efficiently eliminate not only rapidly dividing cancer cells but also slow-cycling or dormant tumor-initiating cells and cancer stem cells—cell populations typically resistant to standard therapies and implicated in relapse.[2]
Amanitin is highly hydrophilic, enabling ADCs to achieve higher drug-to-antibody ratios (DARs) without aggregation and with excellent colloidal stability. Hydrophilicity also means Amanitin is a poor substrate for multidrug resistance (MDR) efflux pumps, helping it overcome a major mechanism of drug resistance that limits many hydrophobic payloads. Furthermore, the use of cleavable linkers ensures the toxin is released only after internalization and lysosomal processing within tumor cells, enhancing selectivity and safety.
Preclinical and Clinical Progress: Heidelberg Pharma’s ATACs
Heidelberg Pharma has pioneered the development of Amanitin-based ADCs (ATACs). Pamlectabart tismanitin, also known as HDP-101 and HDP-103.*
- Pamlectabart tismanitin, includes a humanized, IgG1 kappa monoclonal antibody specifically targeting BCMA, which is heavily overexpressed on malignant plasma cells in multiple myeloma. The payload tismanitin maleimide, a synthetic version of the amatoxin
-amanitin, linked via a protease-cleavable linker, targets BCMA (B-cell maturation antigen) in multiple myeloma. BCMA is a surface protein that is highly expressed in multiple myeloma cells. BCMA antibodies specifically bind to this protein, thereby delivering the toxin Amanitin to the cancer cell. Multiple myeloma is a cancer affecting bone marrow and the second most common hematologic cancer; it represents a major unmet medical need where new, more effective therapies are urgently required. HDP-101 also has potential in further hematologic indications. The investigational agent is being evaluated in a Phase 1/2a clinical study for the treatment of relapsed or refractory multiple myeloma. The first part of this trial is a Phase 1 dose-escalation study to determine a safe and optimal dose of pamlectabart tismanitin for the Phase 2a portion of the study. Pamlectabart tismanitin has been granted Fast Track Designation by the US Food and Drug Administration (FDA). This designation was supported by nonclinical data as well as clinical data from the ongoing Phase 1/2a a study with pamlectabart tismanitin, evaluating the safety and antitumor activity of the candidate in patients with relapsed or refractory multiple myeloma. - HDP-103, targets PSMA in metastatic castration-resistant prostate cancer (mCRPC). The antibody used binds to PSMA, a surface antigen that is overexpressed on prostate cancer cells. This is a promising target for ATAC technology because PSMA shows only very limited expression in normal tissue. Preclinical studies on in vitro and in vivo efficacy, tolerability, and pharmacokinetics have shown that HDP-103 has a promising therapeutic window.
At the Annual Meeting of the American Association for Cancer Research (AACR) held April 17 – 22, 2026, HDP-103, an investigational ADC, demonstrated robust and durable anti-tumor responses in patient-derived xenograft (PDX) models of mCRPC, including those with heterogeneous PSMA expression and high-risk del(17p) mutations.[3]
The data showed that HDP-103 outperformed anti-PSMA Exatecan ADCs, exhibited favorable pharmacokinetics (half-life of 5–10 days), and was well tolerated in primates, with manageable, transient off-target effects limited primarily to the liver and kidneys. These findings are particularly promising for patients with 17p/TP53 deletions, a population with poor prognosis and high unmet need, and for tumors with low or heterogeneous target antigen expression.
Advantages Over Conventional Payloads
- Novel biological target: Inhibition of RNA Polymerase II enables cytotoxicity in both proliferative and quiescent cell populations.
- Resistance bypass: Hydrophilicity and poor MDR substrate profile circumvent classic resistance mechanisms.
- High potency: Microgram quantities suffice for tumor eradication, with a favorable therapeutic window.
- Management of difficult tumors: Efficacy in poor-prognosis settings, such as del(17p) in myeloma and prostate cancer.
- Synthetic accessibility: Advances in stereoselective synthesis and solid-phase peptide methods now make scalable amanitin production feasible.
Challenges and Future Directions
The clinical translation of Amanitin-based ADCs requires ongoing attention to synthetic chemistry, linker optimization, and toxicology, particularly regarding off-target effects in the liver and kidney. Nevertheless, preclinical data indicate a manageable safety profile and a therapeutic index on par with, or exceeding, other ADCs in development or clinical use.
Ongoing and future studies will clarify the full therapeutic potential of Amanitin ADCs, their ability to address minimal residual disease, and their impact on long-term survival in both solid and hematologic malignancies.
Conclusion
Amanitin-based ADCs mark a new era in targeted cancer therapy, introducing a completely novel mechanism—irreversible inhibition of RNA Polymerase II—to the arsenal against both proliferative and dormant cancer cells. By overcoming established resistance pathways and targeting tumor cells regardless of their cell cycle status, Amanitin ADCs hold considerable promise, particularly in refractory and high-risk disease settings. As clinical development progresses, these payloads may transform a deadly mushroom toxin into a cornerstone of precision oncology.
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Note: * The Phase 1 trial of HDP-102 (an anti-CD37 ADC based on cysteine-reactive, site-specific amatoxin-linker constructs for the treatment of Non-Hodgkin lymphoma) was paused due to Heidelberg Pharma’s financial restructuring and strategic reprioritization. In May 2025, the first patient was dosed with HDP-102 in a study center in the Republic of Moldova. This multicenter, multinational, open-label study is designed to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of the investigational agent in patients with relapsed or refractory B-cell malignancies, and to determine the recommended dose for future studies. In addition to Moldova, the trial was also scheduled to be conducted in Israel and selected EU countries. However, in September 2025, after evaluating the first three patients in an initial dose-escalation cohort, the company placed the development program on temporary hold to scale back costs and extend its cash runway. Although the trial remains on a temporary recruitment hold today, patients already enrolled in the first cohort (treated with 40 µg/kg) may continue receiving the trial drug as long as their disease shows no progression.
Clinical trials
Study to Assess Safety of HDP-101 in Patients With Relapsed Refractory Multiple Myeloma – ClinicalTrials.gov ID NCT04879043
References
[1] Ning D, Xue J, Lou X, Shao R, Liu Y, Chen G. Transforming toxins into treatments: the revolutionary role of α-amanitin in cancer therapy. Arch Toxicol. 2024 Jun;98(6):1705-1716. doi: 10.1007/s00204-024-03727-0. Epub 2024 Mar 30. PMID: 38555326.
[2] Pahl A, Lutz C, Hechler T. Amanitins and their development as a payload for antibody-drug conjugates. Drug Discov Today Technol. 2018 Dec;30:85-89. doi: 10.1016/j.ddtec.2018.08.005. Epub 2018 Sep 24. PMID: 30553524.
[3] Decker K, Orlik C, Dranova I, Palfi A, Hechler T, Pahl A, Kulke M. HDP-103, a PSMA targeting amanitin-based ADC, is efficacious even in difficult to treat patient derived xenograft models with heterogenous PSMA expression. In: Proceedings of the 117th Annual Meeting of the American Association for Cancer Research. 2026 April 17-22; San Diego, CA.: AACR; 2026. Abstract nr 5639 / 9
Featured image: Amanita phalloides in la Forêt de la Roche Turpin near Arpajon, France. Courtesy: © 2017 – 2026. This file is licensed under the Creative Commons Attribution-Share Alike 3.0 Unported license. Used with permission.
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