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; Ola M Saad; Shuguang Ma; S Cyrus Khojasteh; Ben-Quan Shen

doi:10.3390/jcm10061323

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

J Clin Med. 2021 Mar 23;10(6):1323. doi: 10.3390/jcm10061323.

Authors

Victor Yip¹, M Violet Lee², Ola M Saad², Shuguang Ma³, S Cyrus Khojasteh³, Ben-Quan Shen¹

Affiliations

¹ Preclinical and Translational Pharmacokinetics and Pharmacodynamics, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
² BioAnalytical Sciences, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
³ Drug Metabolism and Pharmacokinetics, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.

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.

Keywords: antibody–drug conjugate (ADC); distribution, catabolism, and elimination (DME); mass balance; monomethyl auristatin E (MMAE); polatuzumab vedotin (POLIVY).