Natural Products in Antibody-Drug Conjugates and Hybrid Molecules: Leveraging natural product diversity for targeted cancer therapy and complex disease treatment
Zoya Shaikh
https://www.linkedin.com/in/zoya-shaikh-0620a954
Received June 30, 2025. Accepted July 13,
2025.
Reaxion Crucible 2025, 1 (1): e2025004
Abstract
Cancer is one of the top reasons for mortality today. Several research studies are conducted to discover novel and potent treatments for cancer. Antibody-drug conjugates (ADCs) are a significantly remarkable class of oncology therapeutics which is expanding rapidly. Natural products are now gaining popularity for their possible use in ADCs due their specificity. This review article sheds light upon current developments in the discovery of ADCs using natural products. At present, many ADCs combined with natural products have been approved for clinical use, which facilitate precise delivery of therapeutic agents to cancer cells.
The general structure of an ADC consists of three components: a monoclonal antibody (mAb), a linker, and a cytotoxic payload. The mAb identifies and binds to a cancer cell antigen. Linker connects the mAb to cytotoxic payload which selectively kills cancer cells. Cytotoxic payload is the weapon that exerts cytotoxicity when ADCs have entered the cancer cells via internalization. For the compounds to be used as payloads in ADC, they require high potency ((IC50 in picomolar and nanomolar range). This is because only 2% of ADC can reach targeted tumor sites by intravenous administration. Also, the compounds should maintain stability in physiological conditions and must possess suitable function groups for conjugation with the antibody. Presently, DNA damaging agents, inhibitors, and immunomodulators are the types of cytotoxic payloads used for ADCs [6].
Maytansinoids are natural products which obstruct microtubule assembly. Due to high potential they are used in ADCs such as ado-trastuzumab emtansine (Kadcyla) which has received approval for treating HER2-positive breast cancer. Dolastatin 10 is a natural product that hinders microtubule assembly. Its synthetic derivative MMAE is conjugated to the mAb via a protease-cleavable linker. It disrupts microtubule dynamics and selectively kills rapidly dividing cells. MMAE is used in ADCs such as enfortumab vedotin or brentuximab vedotin (Adcetris). These are approved for the treatment of Hodgkin lymphoma and anaplastic large cell lymphoma [1, 5]. Maytansinoids and auristatins are well known classes of cytotoxic compounds which are used as payloads for ADCs in the clinical trial phase. DM1, is another example of maytansinoids which is used as a cytotoxic payload of trastuzumab emtansine. Many other maytansinoid-based ADCs are still under clinical phase. Native lysine chemistry was used to produce T-DM1 where trastuzumab was conjugated with DM1 in a stochastic manner [4]. Some auristatin-class compounds which are widely used in ADCs are still in clinical trials, these have mostly native cysteine conjugation chemistry. Reducing inter-chain cysteines followed by thiolmaleimide conjugation results in relatively lower heterogeneous ADCs compared to native lysine conjugation. Advantageously, native cysteine conjugation has led to the production of six commercially approved ADCs namely Adcetris, Polivy, Padcev, Blenrep, Zynlonta, and Tivdak. This indicates that native cysteine conjugation is feasible for ADC synthesis [1]. Although both maytansinoids and auristatins are tubulin inhibitors, their mode of action is different. While maytansinoids target the maytansine site of microtubes, auristatins (including MMAE) bind the vinca alkaloid site .This mode of action promotes microtube depolymerization. Potential differences in physical characteristics of a maytansinoid and MMAE were examined. MCC-maytansinoid and MC-VC-PAB-MMAE were compared for hydrophobicity by calculated LogP and relative retention time via reverse phase (RP) high-performance liquid chromatography (HPLC; RP-HPLC). The differences in their physical characteristics were further confirmed with the help of differential scanning calorimetry (DSC) analysis and size exclusion chromatography (SEC) [1].
Duocarmycins are DNA-damaging agents which are derived from a natural product CC-1065. These are conjugated to the mAb through a non-cleavable linker. They selectively kill cancer cells by alkylating DNA. Calicheamicin is an enzyme antibiotic that occurs naturally. It can pose a DNA damaging effect by binding the minor groove of DNA leading to double-strand breaks and subsequent apoptosis. Calicheamicin is utilized as a small-molecule toxin in ADCs such inotuzumab ozogamicin and gemtuzumab ozogamicin, which is approved for the treatment of acute myeloid leukemia. Pyrrolobenzodiazepines (PBD) are a class of antitumor antibiotics. These include naturally occurring sibiromycin, anthramycin and tomamycin. PBD binds to the minor groove of the DNA double helix to form interstrand cross-links which inhibit binding of DNA with transcription factors. This induces apoptosis in tumor cells. Interestingly, the inter-strand cross-links induced by PBD do not modify the structure of DNA, hindering repair mechanisms and enhancing the cytotoxic efficacy. In addition, the risk of peripheral neuropathy and systemic toxicity is alleviated. At present, loncastuximab tesirine is the first and the only clinically utilized member of the PBD class of ADCs [2, 3, 6].
Following the significant progress in natural product based drug discovery, many ADCs using natural products have been approved for clinical utilization. As NPs and their derivatives serve as cytotoxic payloads, ADCs facilitate specific delivery of therapeutic agents to cancer cells. However, it is necessary to address the limitations. Improvements focusing on development of cost-effective precursors is expected to enhance rapid synthesis and drug solubilization mechanisms. Continued research and refinement are essential to advancing the therapeutic potential of antibody drug conjugates derived from natural products, in order to achieve greater efficacy and improved safety in clinical applications.
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