Challenges in Antibody-Drug Conjugate (ADC) Development

The next generation of ADCs employs enhanced strategies to achieve optimal stability and specificity, thereby improving therapeutic indices and minimizing off-target toxicity. However, numerous challenges remain, including pharmacokinetics, target-specific payload release, uniform distribution of anti-tumor drugs in tumor regions, adverse effects, and resistance.

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The pharmacokinetic characteristics of ADCs depend on antibody type, antibody properties (murine, chimeric, and humanized), and binding sites. Additionally, pharmacokinetic (PK) properties are influenced by binding affinity, monoclonal antibodies, and cytotoxic payloads, primarily affected by monoclonal antibodies.

Before ADCs are administered to the systemic circulation, intact ADCs, naked antibodies, and free forms of cytotoxic payloads may coexist in the serum.

Two major factors affecting ADC clearance rate are the uncoupling of cytotoxic payloads in antibodies and ADC removal via FcRn-mediated endocytic vesicle recycling.

Moreover, due to the recycling process, naked and intact ADCs have longer half-lives than free cytotoxic payloads. Free cytotoxic payloads are metabolized in the liver and excreted through the urinary system.

Due to all these complexities, establishing pharmacokinetic-pharmacodynamic (PK/PD) models for clinical use remains challenging, but such models can explain interpatient differences and aid in the development of new ADCs.

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Site-Specific Payload Release

Treating solid tumors is more complex than treating hematologic malignancies. Due to the high molecular weight of ADCs, it is challenging for them to penetrate tumor sites. Regarding payload, two primary processes aiding in the delivery of cytotoxic payloads are antigen-dependent endocytosis or antigen-independent phagocytosis. Only a small percentage of the total administered cytotoxic payload reaches tumor sites, hence payloads with low IC50 values should be selected. Highly efficient cytotoxic payloads may induce bystander effects and potentially harm surrounding normal cells.

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Adverse Effects

The most critical factor associated with unpredictable side effects is the premature release of payloads in the systemic circulation. ADC antibodies may elicit immunogenic adverse effects in the body. Thrombocytopenia, anemia, neutropenia, leukopenia, and hepatotoxicity are the most common toxicities observed clinically.

Furthermore, in cases of HER-2 specific ADCs, pulmonary toxicity such as interstitial lung disease (ILD) has been noted. Additionally, various hepatotoxicities were discovered during ADC treatments containing significant amounts of mannose. Therefore, ADCs with low mannose content should be prioritized. Next-generation ADCs should be carefully optimized to develop ADCs with minimal side effects.

Drug Resistance in Antitumor Agents

Another crucial factor to consider is drug resistance. Tumor cells rapidly proliferate, forming new blood vessels. Therefore, due to the rapid proliferation of cells, the distance between cells and blood vessels increases, and irregular blood flow occurs due to poor vascular structure. As a result, conventional drugs cannot reach tumor cells far from blood vessels.

Furthermore, high heterogeneity within tumors is another major factor in drug resistance. Due to the high heterogeneity within tumors, heterogeneous expression of target antigens will occur, leading to the removal or killing of tumor cells expressing only the target antigen. Cells lacking target antigens remain unaffected and will proliferate again, forming tumors without initial target points.

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Targeting Different Types of Tumors

Developing ADCs for specific tumors faces multiple challenges. Specific targets overexpressed on the surface of tumor cells should be selected to avoid adverse effects and bystander effects. However, due to heterogeneity and target diversity, identifying specific targets may be difficult and challenging.

Additionally, according to research reports, selecting specific targets is highly challenging due to the complex microenvironment. Other challenges in treating different tumors include rapid renal clearance, high molecular weight, and rapid internalization.

Due to the high molecular weight of ADCs, it is difficult for them to penetrate solid tumors, especially regions far from blood vessels. However, according to studies, the combination of nanoparticles with antibodies can accelerate the penetration of ADCs into solid tumors while increasing accumulation and internalization capacity.

Next Generation ADCs

To overcome current challenges, some modifications have been made to the components of ADCs and optimized in preclinical and clinical stages. Regarding antibodies, current novel site-specific conjugation methods can help achieve optimized homogeneity. ( Bioconjugation Service at AxisPharm )

Various conjugation methods can minimize off-target toxicity by improving drug delivery to tumor sites to the maximum extent. The high molecular weight of antibodies limits the efficiency of ADCs penetrating blood vessels.

Furthermore, alternative forms of fragmented antibodies or monoclonal antibodies, such as protein scaffolds, peptide-drug conjugates, Fabs, and single-chain variable fragments, help reduce molecular weight. These alternative forms of monoclonal antibodies can improve the efficiency of payload penetration and delivery to tumor sites. It is challenging to deliver ADCs to solid tumors due to antigen barriers.

Therefore, the use of non-internalizing ADCs should be considered to effectively treat solid tumors. These non-internalizing ADCs will release their payloads in the tumor microenvironment, which will then enter cells through diffusion, leading to cell death.

Another major advancement occurs in the adc linker portion.

Furthermore, dual payload ADCs increase the efficacy of ADCs in killing tumor cells by increasing the DAR of ADCs. Additionally, other strategies can be used, such as antibodies and payloads covalently linked through DNA. This strategy reduces the overall hydrophobicity of toxic payloads, with a half-life of 5.8 days. However, its efficacy is not as good as that of classic-linked ADCs.

Future Recommendations of ADCs

ADCs are considered potential solutions for cancer treatment, with the potential to overcome limitations of traditional therapies, but their full potential has not yet been realized in clinical success. One major drawback limiting the use of ADC therapy is striking a balance between maintaining payload efficacy in healthy/off-target tissues and limiting toxicity due to dosing.

Additionally, to emphasize potential future research areas, it can be seen from the literature that ADCs with higher antibody doses lead to significantly improved efficacy, even if they contain the same linker/payload and the same amount of payload. Other increasingly recognized areas include combination therapy, traceless linkers, and improving linker stability.

It should also be noted that the therapeutic effects of ADCs are not limited to tumors. They have been proven to be excellent solutions for treating infections caused by drug-resistant bacteria and have potential for other chronic diseases, such as autoimmune and cardiovascular diseases, by reducing side effects through selective payload delivery.

In recent years, scientists have been working on achieving target-specific drug delivery without internalizing agents/antigens. The basic mechanism of this approach is to induce cell death by mediating signals on the cell surface.

Another technique involves two-step drug delivery, where the antibody first delivers the payload to non-internalizing antigens expressed on the cell surface, followed by systemic delivery of small molecules inducing payload release. Targeting the extracellular matrix, vascular endothelial growth factor may also be a potential idea for disrupting tumor cells.

Original Source: A. Samantasinghar, N. P. Sunildutt, F. Ahmeed, et al., A comprehensive review of key factors affecting the efficacy of antibody drug conjugate. Biomedicine & Pharmacotherapy, 2023.

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Antibody-drug conjugates(ADCs) list Approved by FDA(2000-2023)