Immunoconjugates as an Efficient Platform for Drug Delivery: A Resurgence of Natural Products in Targeted Antitumor Therapy

Abstract

The present review provides a detailed and comprehensive discussion on antibody-drug conjugates (ADCs) as an evolving new modality in the current therapeutic landscape of malignant diseases. The principle concepts of targeted delivery of highly toxic agents forsaken as stand-alone drugs are examined in detail, along with the biochemical and technological tools for their successful implementation. An extensive analysis of ADCs' major components is conducted in parallel with their function and impact on the stability, efficacy, safety, and resistance profiles of the immunoconjugates. The scope of the article covers the major classes of currently validated natural compounds used as payloads, with an emphasis on their structural and mechanistic features, natural origin, and distribution. Future perspectives in ADCs' design are thoroughly explored, addressing their inherent or emerging challenges and limitations. The survey also provides a comprehensive overview of the molecular rationale for active tumor targeting of ADC-based platforms, exploring the cellular biology and clinical relevance of validated tumor markers used as a "homing" mechanism in both hematological and solid tumor malignancies.

Keywords: ADC; C-MET; HER2; Nectin-4; TROP-2; amatoxins; calicheamicins; camptothecins; dolastatins; drug delivery; immunotoxins; maytansinoids; pan-B-cell antigens; targeted antitumor therapy; tissue factor.

Figure 1

Conceptual structure and major components of ADC-based platforms and validated classes of payloads used in ADC design.

Figure 2

Mechanism of action of the major classes of naturally occurring toxins used as payloads in ADC design: (A) Antimitotic agents, (B) DNA-damaging agents, (C) Topoisomerase I inhibitors, and (D) Transcription inhibitors. Created in BioRender. Mihaylova, R. (2024).

Figure 3

Chemical structure of maytansine I.

Figure 4

Chemical structures of the prototype dolastatin 10 and its synthetic analog monomethyl auristatin E (MMAE), used as a microtubule-stabilizing drug in ADCs.

Figure 5

Structure and mechanism of activation of calicheamicin-γ. The process is initiated by a nucleophilic attack in vivo (presumably by glutathione) directed to the trisulfide group, with subsequent intramolecular Michael addition to the reactive α,β-unsaturated ketone. The resulting intermediate spontaneously cycloaromatizes to form aromatic diradical species, abstracting two hydrogen atoms from DNA’s counter-deoxyribose sugars. This transforms the nucleic acid into a highly reactive diradical that, in turn, reacts with O₂, leading to extreme levels (>95%) of DNA fragmentation [59,60].

Figure 6

Chemical structure of anthramycin.

Figure 7

Chemical structures of camptothecin derivatives: Irinotecan undergoes enzymatic conversion by carboxylesterases to its active metabolite SN-38. Deruxtecan carries a tetrapeptide Gly-Gly-Phe-Gly linker, cleaved by lysosomal cathepsins.

Figure 8

Chemical structures of α- and β-amanitin.

Figure 9

Antibody–drug conjugate drug release and mechanism of action. The monoclonal antibody navigates ADC to a target antigen highly expressed on cancer cells (1) and induces its internalization by the formation of an early endosome (2). The latter matures into a late endosome (3), which then fuses with the lysosome (4). Within the lysosome, lysosomal proteases detach the cytotoxic payload from the antibody, allowing it to target cancer cell components such as microtubules or DNA (5,6). The payload, which is permeable through the membrane, can diffuse back into the extracellular matrix, potentially exerting a bystander killing effect on neighboring cells with low or no antigen expression (7). Additionally, cross-binding of the targeted mAb to the Fc receptors (FCRs) on immune cells (natural killer cells and macrophages) recruits immune-mediated antitumor responses, such as antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and antibody-dependent cellular phagocytosis (ADCP), leading to direct cell death (8). Created in BioRender. Mihaylova, R. (2024).

Figure 10

Sustained HER2/HER3 signaling in epithelial carcinomas as a resistance mechanism against HER2-targeting therapies. The tyrosine kinase domain of HER2 mediates the heterophosphorylation and activation of HER3 (dashed arrow), bypassing HER2 blockade. Dual HER2/HER3 inhibition may help overcome compensatory mechanisms of HER3 overexpression, leading to resistance in solid tumors. Created in BioRender. Mihaylova, R. (2024).