**2. Pharmacology**

ADCs allow for a targeted delivery of cytotoxic chemotherapy agents that are too potent to be given in a similar fashion to traditional chemotherapy agents [6]. An advantage of the novel design of ADCs is the efficient delivery of highly toxic chemotherapy afforded by the high specificity of the antibody to the target antigen that is usually highly expressed on cancer cells. ADCs consist of a monoclonal antibodies (mAb) and a cytotoxic payload covalently attached to the mAb via a chemical linker [6].

Designing a successful ADC depends on various factors and properties of each individual component of the ADC [7]. In order to be safe and effective, an ADC needs to be chemically stable in circulation until it reaches the target cancer cell where it will be internalized followed by degradation of the linker or the mAb and subsequent release of the cytotoxic payload in the cell and adjacent cancer cells [7]. Each ADC component plays an important role and should be taken into consideration when designing and developing ADCs. Desired characteristics of ADCs are summarized in **Table 2**.

#### **2.1 The target antigen**

Binding of the antibody to the target antigen is needed to gain access into the cancer cells. This process is referred to as internalization, which occurs via endocytosis [8]. Internalization is required before releasing the cytotoxic payload. It is also desired that the target is an extracellular antigen in order to be recognized by the corresponding antibody. Additionally, the antigen should be non-secreted to prevent ADC binding outside of the tumor vicinity [9]. Secreted antigen in the bloodstream can also lead to significant increase in toxicities. Lastly, the ideal target antigen is highly expressed on cancer cells with minimal to no expression on healthy cells to reduce off-target toxicity [10]. This makes HER2 a great target antigen for T-DM1 and


#### **Table 2.**

*Desired characteristics of ADCs [6].*

T-Dxd [6]. Trophoblast cell-surface antigen 2 (Trop2) is a transmembrane glycoprotein that is highly and differentially expressed in certain solid tumors including breast cancer making it an ideal target antigen for SG [6].

### **2.2 The monoclonal antibody**

Ideal characteristics of mAbs used in ADCs include high affinity to the target antigen, efficient internalization upon binding to the antigen, low immunogenicity, and long plasma half-life [11]. Immunogenicity was a significant challenge associated with mouse-derived antibodies leading to serious adverse events [12]. Current technology employes humanized and fully human mAbs with reduced immunogenicity [11]. The most commonly utilized mAb is immunoglobulin G (IgG) antibody, and specifically IgG1, which exhibits long half-life and can induce antibody-dependent cell-mediated cytotoxicity, phagocytosis, and complement dependent cytotoxicity [13]. The mAb component of T-DM1, T-Dxd and SG is humanized, IgG1 mAb [14–16].
