ADME of Antibody–Maytansinoid Conjugates

Abstract

Abstract. The concept of treating cancer with antibody-drug conjugates (ADCs) has gained momentum with the favorable activity and safety of trastuzumab emtansine (T-DM1), SAR3419, and lorvotuzumab mertansine (IMGN901). All three ADCs utilize maytansinoid cell-killing agents which target tubulin and suppress microtubule dynamics. Each ADC utilizes a different optimized chemical linker to attach the maytansinoid to the antibody. Characterizing the absorption, distribution, metabolism, and excretion (ADME) of these ADCs in preclinical animal models is important to understanding their efficacy and safety profiles. The ADME properties of these ADCs in rodents were inferred from studies with radiolabeled ADCs prepared with nonbinding antibodies since T-DM1, SAR3419, IMGN901 all lack crossreactivity with rodent antigens. For studies exploring tumor localization and activation in tumor-bearing mice, tritium-labeled T-DM1, SAR3419, and IMGN901 were utilized. The chemical nature of the linker was found to have a significant impact on the ADME properties of these ADCs-particularly on the plasma pharmacokinetics and observed catabolites in tumor and liver tissues. Despite these differences, T-DM1, SAR3419, and IMGN901 were all found to facilitate efficient deliveries of active maytansinoid catabolites to the tumor tissue in mouse xenograft models. In addition, all three ADCs were effectively detoxified during hepatobiliary elimination in rodents.

Intracellular Cleavable CpG Oligodeoxynucleotide-Antigen Conjugate Enhances Anti-tumor Immunity

“…The low reductive stability of the disulphide-linked (SS) conjugate is in agreement with other studies that showed SPDPlinked drug conjugates were rapidly cleaved following injection in vivo. 30,[39][40][41] Stability studies performed at pH 7.4, 6, and 5 eliminated a possible pH-triggered cleavage if the conjugates were exposed to the acid environment of the endo-lysosome system. Activation of APCs through binding of CpG to TLR9 as well as cross presentation of antigen epitopes on MHC class I and MHC class II molecules to T cells is crucial for the induction of a strong cellular immune response.…”

Absorption, Distribution, Metabolism, and Excretion Considerations for the Development of Antibody-Drug Conjugates

“…In vitro studies suggest that Lys-MCC-DM1 is metabolically stable and is not an inhibitor of P450 enzymes, whereas DM1 may be metabolized by CYP2D6, CYP3A4, and CYP3A5 and is also a time-dependent inhibitor of CYP3A (Davis et al, 2012). The metabolism of other maytanisinoid-containing catabolites released from ADCs with different drug-linkers were also studied and reviewed (Sun et al, 2011;Davis et al, 2012;Erickson and Lambert, 2012). After administration of brentuximab vedotin in patients, MMAE was the only released drug identified in plasma with peak concentrations in the low nanomolar range (CDER, 2011;Han et al, 2013a).…”

Preclinical Efficacy and Safety Assessment of an Antibody–Drug Conjugate Targeting the c-RET Proto-Oncogene for Breast Carcinoma

“…Assessment of HER2-targeted and CanAg-targeted ADCs with similar or identical linkers has suggested that both ADCs are degraded in the lysosome, and that the major active maytansinoid catabolites from SMCC-DM1 and SPBD-DM4 are lysine-N e -SMCC-DM1 and S-methyl-DM4, respectively (20,32). Whereas the lysine-N e -SMCC-DM1 is charged and membrane-impermeable, S-methyl-DM4 is lipophilic and can reenter target or neighboring cells to induce bystander activity (25); tumors with heterogeneous expression of RET, therefore, may respond differently to Y078-DM1 versus Y078-DM4. Both of these compounds demonstrated potent cytotoxicity in MCF-7/L-RET cells, whereas only Y078-DM4 demonstrated bystander activity and cytotoxicity in MCF-7 cells.…”

“…Thus, the SMCC-DM1 conjugate, which exhibits no bystander cytotoxic activity, should provide a clearer picture of the potential for on-target cytotoxicity (25). An important goal of these studies was to assess the anticipated on-target delivery of the potent microtubule inhibitor to neurons.…”