Antibody-drug conjugates in oncology: insights into Current challenges

KEYWORDS:

• ADCs
• Challenges
• Resistance
• Cancer therapy
• toxicity
• heterogeneity

1. Introduction

Antibody-drug conjugates (ADCs) epitomize a pioneering fusion of biological and chemical therapeutics, signaling considerable potential for advancements in oncology [1,2]. ADCs are constructed around three integral components: an antibody, a stabilizing linker, and a therapeutic payload, all functioning in a coordinated manner [1,2].

The antibody is meticulously crafted to target tumor-associated antigens with pronounced specificity, thereby enhancing the precision of drug delivery [3]. The linker plays an essential role in maintaining the structural integrity of the conjugate, safeguarding the payload from premature release until it reaches its intended site of action. Predominantly comprising cytotoxic agents, the payload delivers the therapeutic impact by targeting and neutralizing malignant cells. Together, these components influence both the pharmacodynamic and pharmacokinetic properties of ADCs [1].

ADCs demonstrate their antitumor effects by inducing adaptive immunity against tumor-specific antigens, increasing T cell infiltration into tumor sites, and strengthening antitumor immune responses [4]. Some ADCs work by blocking PD-1/PD-L1 interactions or activating Toll-like receptor 7/8 (TLR7/8) signaling pathways, thus inducing potent antitumor immune responses; others activate specific immune cells like dendritic cells, T cells, and natural killer cells to promote more effective antitumor immunity [4]. Additionally, ADCs enhance Antibody-Dependent Cell-mediated Cytotoxicity (ADCC) by binding to antigenic epitopes on cancer cells, mediating their killing directly, and stimulating antitumor immune responses further [5].

Extensive clinical evaluations underscore the efficacy of ADCs across a spectrum of malignancies, encompassing breast cancer, lymphoma, leukemia, and solid tumors [3]. These trials have showcased the capabilities of ADCs in both tumor reduction and enhancement of patient survival rates [3]. In vitro studies further corroborate their potent and discriminative cytotoxic prowess across diverse tumor cell lines [3].

Trastuzumab deruxtecan (DS-8201), an ADC targeting HER2-expressing cells, has shown tremendous promise in altering breast cancer treatment paradigms through various clinical trials. One prominent Phase 3 trial demonstrated its efficacy among patients with HER2-low metastatic breast cancer who had undergone previous chemotherapy [6]. The US Food and Drug Administration recently granted accelerated approval to DS-8201a for advanced or unresectable HER2-positive breast cancer cases, based on encouraging trial results, showcasing significant clinical benefits for individuals with metastatic disease [7]. Studies conducted to assess DS-8201a’s antitumor activity across different cohorts of advanced breast cancer patients with varying HER2 expression levels have further highlighted its versatility in treating all forms of HER2-expressing breast cancers [8].

ADCs are currently used in clinics for the treatment of various types of cancers. They have gained approval for clinical use in certain cases, such as sacituzumab govitecan for HR+/HER2- and triple-negative metastatic breast cancer, and trastuzumab deruxtecan for HER2-low metastatic breast cancer [9]. However, the incorporation of ADCs into oncology presents numerous challenges [10]. As we stand at a pivotal juncture in the adoption of these innovative therapies, a comprehensive appraisal of associated challenges becomes essential. The gravity of these challenges holds not only scientific ramifications but also profound implications for patient care and therapeutic progression. Addressing these intricacies is pivotal for refining patient outcomes and for steering the evolution of ADC-centric treatments. Hence, this editorial endeavors to elucidate these challenges while also proposing potential strategies for mitigation.

2. Challenges in development

A primary issue in ADC development is heterogeneity stemming from the conjugation processes. This variation arises from variations in the Drug-to-Antibody Ratio (DAR) and the location of drug attachment on antibodies, which can adversely influence their therapeutic profile and effectiveness [11]. Multiple factors contribute to this diversity. Traditional conjugation methods, such as maleimide-thiol and amine-epoxide couplings, produce varied attachment patterns within an ADC cohort, leading to diverse DAR values [11]. Furthermore, the presence of multiple antigens on tumor cells can result in varied ADC binding sites, leading to inconsistent drug release rates and DAR distribution patterns. Manufacturing challenges, especially inadequate purification, can introduce contaminants that disrupt drug binding, affecting DAR consistency [12]. Such heterogeneity can compromise the therapeutic efficacy of ADCs. For instance, ADCs with low DAR might not effectively combat cancer cells, while unpredictable drug release can elevate drug exposure, increasing the risk of adverse effects such as myelosuppression or hepatotoxicity [11].

The DAR in ADCs is fundamental to their efficacy and safety. While a higher DAR can enhance potency, it might also introduce increased toxicity. Conversely, a lower DAR might emphasize safety at the cost of reduced effectiveness. Thus, determining the optimal DAR involves considering factors like drug toxicity, linker chemistry, tumor specificity, and dosing [1].

3. Toxicity

ADCs have revolutionized oncology by mitigating some conventional chemotherapy side effects, such as hematological toxicity. However, ADCs introduce unique challenges, like interstitial lung disease (ILD) and ocular disorders, that demand special attention [13]. The toxicity of ADCs hinges on multiple factors: payload composition, drug-to-antibody ratio (DAR), linker stability, and target expression in non-cancerous tissues. Intriguingly, many payloads in contemporary ADCs, originally crafted for intravenous delivery, persist in the bloodstream. Some adverse events tied to ADCs echo those from earlier trials with their unconjugated counterparts, hinting at the possible reentry of significant payloads into the bloodstream [13].

A primary hurdle with ADCs is the ‘on-target, off-tumour’ side effects. While ADCs are designed to target cancer cells, they might inadvertently affect benign cells expressing minuscule amounts of the target antigen [14]. This misdirection can cause unintended organ damage. For instance, BR96-doxorubicin in humans can induce vomiting, a side effect absent in its unconjugated form [15].

Adding to these challenges is the ‘off-target, off-tumour’ toxicity. Here, an ADC might exert effects even in the absence of its intended antigen, due to premature drug release or nonspecific uptake, like macropinocytosis. Interestingly, ADCs with similar structures can have divergent toxicity profiles. As an example, enfortumab vedotin might induce dysgeusia, while certain HER2-targeting ADCs pose pulmonary risks but offer reduced cardiac toxicity compared to their unconjugated kin, trastuzumab [16].

Such variations in toxicity might stem from nuanced chemical differences among ADCs. For example, both MMAE and MMAF exhibit distinct ocular side effects, even though they belong to the same category [14]. Moreover, some ADCs remain nontoxic even when their target antigens are found in benign tissues, possibly due to antigen inaccessibility.

The unpredictable behavior of ADCs, influenced by their uptake in non-cancerous cells via diverse mechanisms, further complicates matters [14]. Specific ADCs may exhibit different adverse effects based on the cancer type addressed.

4. Resistance

Resistance to ADCs arises from a plethora of mechanisms that might undermine therapeutic efficacy. A paramount concern is antigen expression. Diminished antigen presence on cancer cells curtails ADC binding [17]. Moreover, not all tumors consistently shed the extracellular domain of the target antigen, a process that can sequester ADCs [17]. In the context of HER2, this shedding yields both a truncated extracellular domain and an intracellular p95HER2 domain [18]. Furthermore, the glycoprotein mucin 4 (MUC4) has the potential to hinder trastuzumab’s binding efficacy, and the challenge is intensified by the presence of intratumoral heterogeneity [19].

T-DM1 resistance often stems from imbalances in HER2-related pathways like PI3K/Akt and mTOR. Low PTEN expression can worsen this, leading to heightened resistance mechanisms.

Pharmacodynamic challenges include unstable linkers causing premature drug release and lysosomal function issues affecting drug liberation. Altered protease activity can also compromise drug release in certain ADCs [20].

Efflux pumps like P-glycoprotein and MRP1 play a key role in drug resistance, particularly in T-DM1. Lastly, mutations in payload targets like TOPI and interactions with entities like cyclin B1 add another layer of complexity [20].

5. Expert opinion

This editorial provides insight into a concerning problem with antibody-drug conjugates (ADCs), with several contributing variables from various vantage points. Moreover, this investigation highlights the necessity for additional extended research to completely investigate ADCs issues. The main challenges in developing effective ADCs are not only in overcoming the resistance to ADCs, but also the selection of chemically stable linkers, suitable target antigens, and extremely potent cytotoxic medicines; recognizing these key determining elements may offer guidance for the design of effective ADCs complex molecules.

5.1. Identification of antigen target

The selection and validation of appropriate antigenic targets for the antibody component is a critical issue in the fabrication of ADCs for oncology. Antigen selection must take several things into account. Target antigens ought to preferably have significant expression in tumors and limited expression in normal tissues, or at least expression confined to a certain tissue type, to decrease off-target damage and yield an appropriate therapeutic index for the ADCs [21]. To be susceptible to the antibody, the target antigen must be expressed on the outermost layer of the cell. It ought to be an internalizing antigen, so that upon binding, the ADCs are carried into the cell and may exert its cytotoxic activity [22].

5.2. Linker design and optimisation

Effective linker design balances stability in circulation with successful cell-targeted disintegration. Research focuses on improving ADC solubility and drug-antibody ratio (DAR), and combating resistance from drug-expelling proteins [23]. Strategies include conditional release via cleavable linkers, enhancing or restricting the bystander effect through charge-based linker-drug compounds. The bystander effect allows ADCs to kill nearby cells, regardless of antigen presence, based on the linker’s charge [24]. Cleavable linkers can be sensitive to lysosomal proteases, acid, or reducible by glutathione.

5.3. Selection of cytotoxic medicines

Numerous chemotherapeutic medicines employed in ADCs are hydrophobic and likely to generate antibody aggregation, which must be avoided in order to provide a prolonged shelf life while also limiting quick rate of clearance and immunogenicity. The active must also keep its efficacy when changed for linking, have adequate solubility in aqueous environment, and be durable as a conjugate in aqueous preparation. Furthermore, the medicine must be synthetically obtainable and acquired through a cost-effective technique according to good manufacturing practise settings [23].

5.4. Avoiding ADCs resistance

Resistance to ADCs is a complex, ongoing research area. Increased drug extrusion by upregulation of drug-efflux pumps is one of the most typical ways [17]. Potential solutions include bispecific antibodies that target multiple epitopes to improve internalization and degradation [18]. ADCs may also be made more potent by regulating the quantity of payload released; the higher the payload release rate, the more potent the ADCs become. Finally, combination treatments are another strategy for overcoming resistance; combining two chemotherapeutic agents has been proven to have a good influence on tumor suppression and tumor regression [20].

5.5. Concluding remarks

ADCs represent an innovative class of cancer therapies with significant potential to address many shortcomings associated with traditional chemotherapy regimens. However, they still face major obstacles, such as heterogeneity, toxicity, and resistance issues. Further research is essential for developing more effective and safer ADCs to enhance patient outcomes.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.