The development of antibody-drug conjugate (ADC) therapies has progressed rapidly in recent years, with 15 products approved worldwide. It is estimated that the global market share for ADCs will exceed $15 billion by 2030. The popular belief is that ADCs can increase the tolerated dose of a drug while lowering its minimum effective dose, but a growing body of clinical evidence shows that tolerated doses of ADCs do not differ significantly from those of corresponding small molecule drugs. However, some ADCs may improve efficacy when used near the maximum tolerated dose.
To raise awareness of the opportunities and challenges of existing ADC applications, Raffaele Colombo and Jamie R. Rich of Zymeworks, Canada, recently published a review article in Cancer Cell, The therapeutic window of antibody drug conjugates: A dogma in need of revision, looking at the next generation of ADC development.
Principle of ADCs
The principle of ADC is to increase the therapeutic window of a drug by linking a monoclonal antibody to a toxic therapeutic small molecule drug to deliver the toxicant precisely to the tumor site without affecting normal tissue. Preclinical data suggest that coupling a drug to an antibody results in a decrease in its minimum effective dose (MED) and an increase in its maximum tolerated dose (MTD). However, clinical data do not support this idea. ADC is essentially the same as the MTD of small molecules in humans. Therefore, the theory of an allegedly expanded therapeutic window from ADCs is likely incorrect, although certain ADCs can lead to significant improvements in the therapeutic efficacy of the drug when used close to the MTD.
In clinical trials, the MTD of a drug is typically measured in Phase I clinics and used to determine the recommended dose (RP2D) design for Phase II clinics. The ADCs currently approved and in clinical testing use structurally similar small molecule drugs that have been previously tested for MTD. Comparing the clinical doses of the two requires harmonization to the same units, as both have different molecular weights, drug/antibody ratios (DARs), and are proposed to be harmonized to mg/kg. after unit harmonization, the authors compared the 10 approved ADCs and all currently tested ADCs and found that they failed to extend the therapeutic window. And in fact, it has been reported as early as a decade ago that T-DM1 clinical data did not correlate with preclinical data in terms of therapeutic window [1].
Why then is there no significant difference between the MTD of ADC and small molecule drugs?
The likely reason is that the primary role of antibodies is to protect the coupled drug from clearance and metabolism. After the small molecule is delivered to the target cell and absorbed by the antibody, subsequent metabolism remains through the classical drug metabolism pathway. In addition, the linker of ADC may be cleaved extracellularly and become one of the sources of drugs in the circulatory system. In addition, most of the available ADCs are prepared chemically by thiol-maleimide, which undergoes an anti-Mixture reaction to dissociate the entire linker from the antibody. Most (50%-75%) of these ADCs have dissociated after more than 7 days in the plasma, and the dissociated linker continues to react with other thiols in the plasma to form a new linker, usually albumin. The long half-life of albumin in the blood can lead to some toxicity of the coupled drug due to non-specific release and prolonged half-life, while of course enhancing the therapeutic effect on tumors that can absorb albumin. However, little is known about the role of albumin in drug toxicity and efficacy [2].
The use of PEGs as linkers between antibodies and payload molecules can improve ADC loading. PEGs create a protective shield that wraps the ADC payload from its microenvironment, improving solubility and stability. Other benefits include reduced aggregation, resulting in lower immunogenicity, improved pharmacokinetics, longer cycle times and reduced toxicity. Biopharma PEG offers a variety of PEG linkers to facilitate antibody-drug conjugate (ADC) development programs. All PEG linkers are >95% pure and they are an essential component of a successful ADC.
Have ADCs improved over their drug load?
On the one hand, it is important to see the fact that 15 ADCs have been approved, highlighting the importance of this therapy; but on the other hand, more than 100 ADCs have been terminated from development, indicating that identifying the right combination of antibody, target, and linker is still a huge challenge. In clinical testing of oncology drugs, MTD is considered the most relevant indication for drug activity measurement, but MED is usually not measured because clinical phase II and III endpoints are determined based on efficacy rather than MED. the metrics for FDA approval of oncology drugs have changed from objective remission rate (ORR) to more direct clinical benefit, such as progression-free survival (PFS) and overall survival (OS). Although ORR does not fully predict survival benefit, ORR is directly linked to drug efficacy and is the most common surrogate endpoint for accelerated FDA approval. A clinical trial of a controlled ADC versus its loaded small molecule showed an ORR of 42% for the ADC versus only 12.5% for the small molecule. Current clinical data support the superior ORR of multiple ADCs over their corresponding small molecule drugs.
Coupled antibodies can alter the pharmacokinetics (PK) of the drug and prolong the drug half-life by avoiding renal clearance, for example. However, ADCs face similar problems as other biomolecular drugs, such as on-target off-tumor (OOT) and non-specific clearance, difficulty in passing through capillary walls, difficulty in getting inside tumor tissue, and binding site barriers. It has been suggested that less than 1% of ADCs can reach tumors in humans. Therefore, there should be other reasons for the increased efficacy of ADC. by analyzing PK models of approved ADC [3], Tarcsa et al. confirmed that its efficacy depends on other mechanisms, such as prolonging the effective dose level of its drug delivery in the blood. Therefore, the degree of drug-loaded bystander activity, the chemistry of the linkage (whether it is easy to depolymerize) and the type of linker are key parameters that should be considered in ADC design, and it is necessary to design clinical trials of different linkage ADCs for specific targets to determine the optimal linkage.
Recent clinical data suggest that circulating drug carriers can produce baseline antitumor effects. Considering the effective therapeutic effect of ADC in patients with low or no expression of tumor antigens in clinical tests, the authors hypothesized that the targeted component of ADC (i.e., ADC direct delivery) could enhance the baseline therapeutic effect of its carrier drug itself, a hypothesis also supported by clinical data.
Finally, confirming the inability of ADC to enhance the MTD of the drug, the authors give some key factors to consider to improve its effectiveness and tolerability and implications for the field.
(1) The tolerated dose of one ADC is not superior to other ADCs prepared by the same technology, provided that the drug delivery, linker, DAR, and linkage method are all unchanged.
(2) Is there a more acceptable explanation for the fact that ADCs are roughly equivalent to their drug-loaded TMDs?
(3) In-depth analysis of the PK/PD profile of ADCs is necessary to optimize their clinical dose design.
(4) Insight into the mechanism of action of clinically activated ADCs and the relationship between the structural components of ADCs and their PK/PD will help in the design of next-generation ADCs.
(5) More predictive in vitro and in vivo models are urgently needed to determine whether an ADC has the potential to be transmissible.
(6) New ADC coupling sites, linker chemistry, and linker technology are still to be supported by clinical data to judge their effectiveness.
(7) Toxicity of ADCs to the eye and lung needs to be urgently recognized and addressed.
(8) Optimization of other drug-forming characteristics of the carrier drug (e.g., solubility, permeability, metabolic stability, and transporter substrate profile) could help improve the clinical attrition rate of ADCs.
(9) Matching of antibodies and drug carriers should be determined based on tumor type, site, and antigen expression level.
(10) Attention should also be paid to the potential hazards associated with off-target delivery of novel drug carriers, such as steroids, PROTAC, TLR agonists, STING agonists, viral peptides, RNA, etc., via antibodies.
(11) A variety of ADCs have been shown to cause immune cell death (ICD) [4], but the mechanism remains to be studied.
(12) It is currently popular to combine ADCs with immune detection site inhibitors or other toxic agents, and clinical benefits have indeed been observed, but there is no evidence to support whether there is a synergistic or superimposed effect between the two treatment regimens [5].
References:
- Poon, K.A., et al. (2013). Preclinical safety profile of trastuzumab emtansine (T-DM1): mechanism of action of its cytotoxic component retained with improved tolerability. Toxicol. Appl. Pharmacol. 273, 298–313.
- Nilsen, J., et al. (2018). Human and mouse albumin bind their respective neonatal Fc receptors differently. Sci. Rep. 8, 14648.
- Tarcsa, E., et al. (2020). Antibody-drug conjugates as targeted therapies: are we there yet? A critical review of the current clinical landscape. Drug Discov. Today Technol. 37, 13–22.
- Nessler, I., et al. (2021). Key metrics to expanding the pipeline of successful antibody-drug conjugates. Trends Pharmacol. Sci. 42, 803–812.
- Palmer, A.C., et al. (2022). Predictable clinical benefits without evidence of synergy in trials of combination therapies with immune-checkpoint inhibitors. Clin. Cancer Res. 28, 368–377.
