Present Situation, Challenge, Opportunity and Future of ADC

At present, a variety of antibody-coupled drugs (ADC) have been approved for the treatment of solid tumors, and have been rapidly extended to indications of multiple tumor types. For example, anti-HER2 ADC, anti-Trop-2 ADC, anti-nectin-4 ADC, etc.

In March, 2022, CA (CA: A Cancer Journal for Clinicians, Impact Factor: 508.702) summarized the characteristics and clinical data of ADC drugs approved by FDA for solid tumors, and discussed the challenges, opportunities and future they faced.

History

ADC is a class of new drugs that deliver chemotherapy drugs to solid tumors. ADC consists of three parts: monoclonal antibody, linker and payload. ADC entered tumor clinical trials in 1980s, but it did not show survival benefits, but observed obvious toxicity. This situation lasted for about 20 years until the CD33 targeted drug gemtuzumab ozogamicin was approved (in 2000, the first indication was relapsed or refractory acute myeloid leukemia), which was also the first ADC approved by FDA. In 2013, HER2 targeted drug adotrastuzumab emtansine (T-DM1) went on the market, which was also the first ADC approved for the treatment of solid tumors. Since then, the pace of ADC research and development has gradually accelerated.

Inventory of ADC approved for solid tumor

At present, ADCs approved by FDA include: T-DM1 and T-DXd for the treatment of HER2 positive breast cancer; T-DXd in the Treatment of HER2 Positive Gastric Cancer; Gosartuzumab in the treatment of triple negative breast cancer (TNBC): Gosartuzumab and enfortumab vedotin in the treatment of urothelial carcinoma; Tisotumab Vedotin is used in the treatment of cervical cancer. The data of each ADC (drug structure, indications, clinical studies, efficacy and safety results) are summarized in detail in the original review.

Antitumor Activity of ADC

Up to now, the expression of HER2, Trop-2, nectin-4 and many other antigens has been described in many tumor types, which puts forward the hypothesis that ADC targeting these antigens can achieve a wide range of anti-tumor activities in solid tumors. The following figure shows the activity of three new ADC (T-DXd, gostuzumab, trastuzumab duocarmazine) in multiple tumor types, which is expressed by objective remission rate (ORR). [Note: The highest ORR observed in clinical trials of the same histological type; Labeling is not applicable (NA) if data are not available for this histological type or if the number of patients is less than 10. ] 

ADC toxicity: "Targeted chemotherapy" is still chemotherapy

The main purpose of combining cytotoxic drugs with antibodies is to achieve targeted delivery of payloads, expand the treatment window and reduce the toxicity related to chemotherapy. For a variety of reasons, the ADC currently available only partially achieves this goal. As mentioned earlier, ADC structure consists of three parts: antibody, linker and load. The relative proportions of these three components are different for different ADC. Pharmacokinetics showed that the DAR of T-DM1 in solid tumor ADCs was small (note: average 3.5), which may partly explain the reason of its mild toxicity. For the same reason, the obvious toxicity of new ADCs can be partially explained (note: DAR of T-DXd and gostuzumab is 8).

In fact, the use of higher DAR and cutable connectors may be related to a higher percentage of free load diffusing into the cycle. Compared with T-DM1, the dose of cyclic free load observed after using T-DXd and gostuzumab increased by 10 ~ 100 times. Moderate to severe neutropenia, hair loss and gastrointestinal side effects have been observed in most clinical trials of new ADCs (including T-DXd, gostuzumab, enfortumab vedotin and trastuzumab duocarmazine). In this case, pharmacogenomics detection is also being applied to ADC treatment. For example, in patients with TNBC and homozygous UGT1A1*28 allele, the incidence of severe neutropenia observed after using gostuzumab has more than doubled, suggesting that pharmacogenomics detection may be helpful in dose selection of this (and possibly other) ADC. It is worth noting that pharmacological differences between different loads may affect the overall toxicity of ADC.

However, free loading does not fully explain all the toxicity observed by ADC. In fact, "on-target, off-tumour" is also an important factor of ADC toxicity, and other mechanisms related to toxicity are not fully understood. For example, interstitial lung disease (ILD) associated with ADC is of concern. Data show that up to 15% of patients who participated in T-DXd or datopotamab-DXd test developed ILD, of which 2% ~ 3% were fatal. Similarly, trastumab duocarmazine has shown ILD risk, with 7.8% of patients with any level of ILD in the TULIP trial, including fatal cases. Studies on cynomolgus monkeys show that drug uptake by alveolar macrophages may be the cause of this toxicity, rather than free load.

It should also be noted that histological specific factors, potential diseases and previous treatment of patients may be the influencing factors of toxicity.

Future prospects

The selection of target antigen is very important. At present, a computer strategy is being developed to use RNA sequencing and protein expression data to predict the most reasonable target antigen, provide information for future ADC design, improve tumor antigen map and determine histology that is most likely to benefit from specific ADC.

It is worth noting that the design of load is no longer limited to chemotherapy drugs. For example, early clinical trials of radionuclide-bound ADC are underway, aiming at selective delivery of radioactive payload. In addition, immunostimulating molecule binding ADC is still being explored to induce targeted anti-tumor immune response and/or synergistic effect with immune checkpoint inhibitors; In addition, ADC combined with double different chemotherapy drug loads is also undergoing early trials.

Another strategy worth trying is to bind payloads to bispecific antibodies. For example, anti-HER2 bispecific antibody zanidatamab has shown ideal anti-tumor activity and tolerance in > 10 tumor types expressing HER2. A new compound ZW49 was obtained by combining loaded auristatin with zanidatamab, which is a bispecific ADC in the early stage of research and development. This combination may further improve the anti-tumor activity of zanidatamab.

Finally, the combination of ADC and other anti-tumor drugs may potentially improve the activity of ADC. For example, the activity of immunotherapy drugs can be improved by ADC-mediated immunogenic cell death, or the up-regulation of ADC target antigen can be induced by pharmacology. A variety of combined treatment strategies with ADC are being studied clinically in a variety of solid tumors.

Summary:

Less than ten years after the first ADC was approved for solid tumors, we are experiencing unprecedented development of this treatment strategy. The improvement of engineering technology endows new ADCs with higher efficacy and specificity, thus expanding the range of targeting solid tumors. Novel ADCs are active in a variety of malignant tumors expressing specific antigens, reflecting the prospect of targeted therapy unrelated to histology. At the same time, it also poses several challenges to new ADCs, including: the best biomarker for predicting ADC activity, drug toxicity management and so on. If these challenges can be fully addressed, we can greatly expand our ability to treat tumors and bring benefits to patients with various cancer types.

References 

CA Cancer J Clin.2022; 72 (2): 165-182. 

Note: The pictures used in the tweet are all from this reference