So far, a total of 16 ADC drugs have been approved worldwide, and one (trastuzumab duocarmazine) is still in the stage of applying for listing. In recent years, with the significant increase in the number of IND applications submitted to the FDA, the ADC field has been expanding. At present, more than 900 different ADCs are in different stages of research and development, and the main indications are hematological malignant tumors and solid tumors.
In the research and development of ADC drugs, despite the use of antibodies against tumor-specific and/or tumor-overexpressed antigens, the dose-limiting toxicity (DLT) of suboptimal treatment doses is still a major challenge to the clinical application of ADC. DLT leads to a relatively narrow treatment index (TI), which is also the main reason to limit the increase in ADC dose to achieve maximum efficacy.
Although the toxicity of ADC is thought to be mainly due to the payload, the mechanism of ADC uptake in non-targeted normal cells to transfer the cytotoxic payload is unclear. Only a small amount of ADC accumulation occurs in the human target (tumor) (approximately 0.1% of the dose per gram of tumor). Most of ADC is still in systemic circulation or distributed in normal tissues and is absorbed and catabolized, resulting in toxicity to normal cells.
Even at relatively small levels, the expression of ADC-targeted antigens in normal tissues may result in ADC target-dependent uptake and secondary toxicity. For instance, the dose-limiting effect of BMS-182248-01 on gastrointestinal toxicity (hemorrhagic gastritis) is related to the expression of Lewis-Y target antigens on normal gastric mucosal cells.
It should also be noted that the expression of target antigens in normal cells does not usually predict the toxicity of ADC. For example, despite the clinical toxicity of trastuzumab emtansine (TDM1, KADCyla®, and ADC targeting HER2) and high levels of HER2 expression in vital organs such as the heart and kidney, there is no evidence that T-DM1 is associated with these organ toxicity. Severe thrombocytopenia is a common DLT in T-DM1. Because there is no expression of HER2 on platelets in systemic circulation or on megakaryocytes that produce platelets, this toxicity is largely considered to be a target-independent effect.
In addition to the expression of target antigen, the internalization rate of target antigen, circulatory/transkinetic dynamics, intrinsic sensitivity to payload, and in vivo distribution of ADC to normal cells/tissues may determine ADC toxicity. In general, tissues with high perfusion and vascular leakage (incomplete and/or missing basement membrane), such as the liver, bone marrow, and spleen, are expected to have higher IgG/ADC distribution and exposure than other normal tissues.
Some ADCs have the same payload and connectors, but have similar maximum tolerance doses (MTDs) for different antigens and show similar toxicity in normal cells and tissues. The most common ADC toxicity has nothing to do with the expression of target antigens. For example, neutropenia is generally thought of as having the most MMAE-based DLT (with divisible connectors). Similarly, the ocular (corneal) toxicity is multiple ADC DLT containing DM4.
In addition, the ocular toxicity of different targets was observed in multiple MMAF-based ADCs. It is concluded that the toxicity of ADC is a miss effect to a large extent, which further indicates the potential effect of drug linker combinations (ADC platform) on specific miss toxicity. Therefore, there is good reason to believe that the three components of ADC (namely, monoclonal antibodies, payloads, and connectors) can lead to normal cell or tissue toxicity.