**2.5 The bystander effect**

The bystander effect is described with certain ADCs that exhibit an antitumor activity against cancer cells located near those expressing the targeted antigen [39, 40]. In other words, the cytotoxic payload can diffuse through the target cell membrane to and kill adjacent cancer cells that are antigen negative. Properties that allow for bystander effect include having cleavable linkers and cell membrane permeable cytotoxic payload. These properties allow the payload to diffuse to neighboring cells. ADCs with bystander effect may not require high expression of the target antigen to be effective. Due to having cleavable linkers and membrane permeable payloads, both T-Dxd and SG exhibit bystander effect. Conversely, T-DM1 does not exhibit the bystander

*Antibody Drug Conjugates DOI: http://dx.doi.org/10.5772/intechopen.110804*

effect. The release of payload in T-DM1 requires complete digestion of trastuzumab followed by release of the metabolite, lysine-MCC-DM1, which is charged under physiologic pH and thus is not cell membrane permeable. Therefore, T-DM1 can only exert cytotoxic effect against antigen positive cancer cells (i.e., HER2 positive cells) [6]. Unlike T-DM1, T-Dxd has demonstrated efficacy in both HER2 overexpressing cancer cells as well as cells that are HER2 low due to the bystander effect [41, 42].

### **3. Pharmacokinetics and pharmacodynamics**

Pharmacokinetic (PK) properties of T-DM1, T-Dxd, and SG including metabolism and elimination are described in **Table 3**. The mAb component is expected to be catabolized into small peptides and amino acids via the same pathways used to degrade endogenous IgG monoclonal antibodies [14–16].

#### **3.1 T-DM1**

Based on population PK studies, covariates that can impact T-DM1 clearance include body weight, albumin, AST, and baseline trastuzumab concentrations. However, with the exception of weight, other covariates are unlikely to have meaningful impact on clearance. Exposure to T-DM1 was not shown to be affected by mild (CrCl 60–89 mL/min) or moderate (CrCl 30–59 mL/min) renal impairment. Patients with severe renal impairment (CrCl <30 mL/min) were not included in clinical trials. Therefore, no renal dose adjustment is required, but no recommendations can be made for use of T-DM1 in severe renal impairment due to lack of data in this patient population [14].

DM1 is primarily hepatically metabolized via CYP3A4 and to a lesser extent by CYP3A5. Serum concentrations of DM1 in patients with mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment were comparable to those achieved in patients with normal liver function. T-DM1 was not studied in patients with severe hepatic impairment (Child-Pugh C). Based on this, no dose adjustment is required in mild or moderate hepatic impairment and no recommendations can be made for patients with severe hepatic impairment.


*Abbreviations: ADCs, antibody drug conjugates; BCRP, breast cancer resistance protein; OATP, organic anion transporting polypeptides; P-gp; p-glycoprotein; SG, sacituzumab govitecan; T-DM1, ado-trastuzumab emtansine; T-Dxd; fam-trastuzumab deruxtecan; UGT1A1, UDP glucuronosyltransferase 1 family, polypeptide A1.*

#### **Table 3.**

*ADCs pharmacokinetic properties [14–16].*

In a population-based PK study, age and race had no clinically meaningful impact on T-DM1 exposure. While there are no safety studies of T-DM1 in pregnant women, cases of oligohydramnios presenting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death are reported with use of trastuzumab [14]. Given the mechanism of action of DM1 and sensitivity of rapidly dividing cells to its cytotoxic antimicrotubular effect, animal studies suggest that T-DM1 has the potential to cause embryotoxicity and teratogenicity [14]. Women of childbearing age should be tested for pregnancy prior to initiating treatment. Women of childbearing age and men with female partners of reproductive potential should use effective contraception during treatment and for 7 months and 4 months after the last dose of T-DM1, respectively. Women should also be advised to avoid breastfeeding during treatment and for 7 months after the last dose of T-DM1 [14].

#### **3.2 T-Dxd**

Based on population PK studies, there was no difference observed in exposure to Dxd in patients with mild (CrCl 60–89 mL/min) or moderate (CrCl 30–59 mL/min) renal impairment. Patients with severe renal impairment (CrCl <30 mL/min) were not included in clinical trials. Patients with moderate renal impairment should be monitored for interstitial lung disease more frequently. No recommendations can be made for use of T-Dxd in patients with severe renal impairment due to lack of data in this patient population [15].

T-Dxd is primarily hepatically metabolized via CYP3A4. There was no difference in exposure to T-Dxd in patients with mild hepatic impairment (total bilirubin ≤ ULN and any AST > ULN or total bilirubin >1 to 1.5 times ULN and any AST) compared to patients with normal hepatic function. PK of T-Dxd in patients with moderate to severe hepatic impairment is not known. T-Dxd dose adjustment is not required in patients with mild to moderate hepatic impairment, but these patients need to be monitored more closely for adverse events related to Dxd. No significant difference in exposure to Dxd was observed for age or race [15].

Given the known risk of the trastuzumab component of T-DXd to the fetus as described above and Dxd cytotoxic effect on actively diving cells, T-Dxd is considered genotoxic. Women of childbearing age should be tested for pregnancy prior to initiating treatment. Women of childbearing age and men with female partners of reproductive potential should use effective contraception during treatment and for 7 months and 4 months after the last dose of T-Dxd, respectively. Women should also avoid breastfeeding during treatment and for 7 months after the last dose of T-Dxd [15].

#### **3.3 SG**

SN-38 is metabolized via uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) to the inactive glucuronide metabolite, SN-38G, which is then eliminated by biliary excretion [43]. Based on population PK studies, there was no difference observed in exposure to SN-38 in patients with mild or moderate renal impairment, and renal elimination of SN-38 is found to be minimal [16]. Therefore, no renal dose adjustment is required for SG for mild or moderate renal function impairment. No recommendations can be made for use of SG in severe renal impairment due to lack of data in this patient population [16]. There is no difference in exposure to SG between patients with mild hepatic impairment compared to patients with no hepatic impairment. SG PK is not known for patients with severe hepatic impairment [16].


*Abbreviations: HER2, human epidermal growth factor receptor 2; HR+, hormone receptor positive; IV, intravenous; SG, sacituzumab govitecan; T-DM1, ado-trastuzumab emtansine; T-Dxd; fam-trastuzumab deruxtecan; TNBC, triple negative breast cancer.*

#### **Table 4.**

*Dose and administration [14–16].*

There was no significant impact of age or race on PK properties of SG and exposure to SN-38 [16]. Given the mechanism of action of SN-38 and its effect on rapidly dividing cells, SG is considered teratogenic and genotoxic [16]. Women of childbearing age should be tested for pregnancy prior to initiating treatment. Women of childbearing age and men with female partners of reproductive potential should use effective contraception during treatment and for 6 months and 3 months after the last dose of SG, respectively. Women should also avoid breastfeeding during treatment and for 1 months after the last dose of SG (**Table 4**) [16].
