Preclinical Characterization of the Distribution, Catabolism, and Elimination of a Polatuzumab Vedotin-Piiq (POLIVY®) Antibody-Drug Conjugate in Sprague Dawley Rats.

Victor Yip,M Violet Lee,Shuguang Ma,S Cyrus Khojasteh,Ola M Saad,Ben-Quan Shen

doi:10.3390/jcm10061323

Abstract

Polatuzumab vedotin (or POLIVY®), an antibody–drug conjugate (ADC) composed of a polatuzumab monoclonal antibody conjugated to monomethyl auristatin E (MMAE) via a cleavable dipeptide linker, has been approved by the United States Food and Drug Administration (FDA) for the treatment of diffuse large B-cell lymphoma (DLBCL). To support the clinical development of polatuzumab vedotin, we characterized the distribution, catabolism/metabolism, and elimination properties of polatuzumab vedotin and its unconjugated MMAE payload in Sprague Dawley rats. Several radiolabeled probes were developed to track the fate of different components of the ADC, with 125I and 111In used to label the antibody component and 3H to label the MMAE payload of the ADC. Following a single intravenous administration of the radiolabeled probes into normal or bile-duct cannulated rats, blood, various tissues, and excreta samples were collected over 7–14 days post-dose and analyzed for radioactivity and to characterize the metabolites/catabolites. The plasma radioactivity of polatuzumab vedotin showed a biphasic elimination profile similar to that of unconjugated polatuzumab but different from unconjugated radiolabeled MMAE, which had a fast clearance. The vast majority of the radiolabeled MMAE in plasma remained associated with antibodies, with a minor fraction as free MMAE and MMAE-containing catabolites. Similar to unconjugated mAb, polatuzumab vedotin showed a nonspecific distribution to multiple highly perfused organs, including the lungs, heart, liver, spleen, and kidneys, where the ADC underwent catabolism to release MMAE and other MMAE-containing catabolites. Both polatuzumab vedotin and unconjugated MMAE were mainly eliminated through the biliary fecal route (>90%) and a small fraction (<10%) was eliminated through renal excretion in the form of catabolites/metabolites, among which, MMAE was identified as the major species, along with several other minor species. These studies provided significant insight into ADC’s absorption, distribution, metabolism, and elimination (ADME) properties, which supports the clinical development of POLIVY.

Highlights

Our studies demonstrated that polatuzumab vedotin had a stable linker in circulation and confirmed that the antibody component of the antibody–drug conjugate (ADC) dictated the overall ADC disposition in rats
Upon the distribution/internalization into the tissues, ADC underwent catabolism to release monomethyl auristatin E (MMAE) and several other catabolites over time, which were mainly eliminated via the biliary–fecal route, with a minor fraction through the urine in rats
These results imply that the liver plays a more important role than the renal clearance in the elimination of polatuzumab vedotin catabolites; additional hepatic impairment studies in patients might provide clinicians with further insight

Summary

Introduction

The development of antibody–drug conjugates (ADCs) has accelerated in recent years, resulting in many advancements to this class of therapeutic molecules [1]. Polatuzumab vedotin, which was approved for treating diffuse large B-cell lymphoma (DLBCL), consists of an immunoglobulin G1 (IgG1) monoclonal antibody (mAb) against the antigen Cluster of Differentiation 79B (CD79b, polatuzumab) conjugated with a payload of monomethyl auristatin E (MMAE, vedotin) using a protease-labile linker, namely, maleimidocaproylvaline-citrulline-p-aminobenzyloxycarbonyl (MC-vc-PAB) [2,3]. The pharmacokinetics (PK) of polatuzumab vedotin in rodents and cynomolgus monkeys were described by Li et al [4], who showed that the concentration–time profile of polatuzumab vedotin was very similar to that of unconjugated polatuzumab antibodies, with a short distribution phase followed by a long elimination phase. The characterization of the absorption, distribution, metabolism, and elimination (ADME)

Methods

Results

Discussion

Conclusion