The Dolaflexin-based Antibody-Drug Conjugate XMT-1536 Targets the Solid Tumor Lineage Antigen SLC34A2/NaPi2b

• Published in: Molecular cancer therapeutics 2021-05, Vol.20 (5), p.896-905
• Main Authors: Bodyak, Natalya D, Mosher, Rebecca, Yurkovetskiy, Aleksandr V, Yin, Mao, Bu, Charlie, Conlon, Patrick R, Demady, Damon R, DeVit, Michael J, Gumerov, Dmitry R, Gurijala, Venu R, Lee, Winnie, McGillicuddy, Dennis, Park, Peter U, Poling, Laura L, Protopova, Marina, Qin, LiuLiang, Stevenson, Cheri A, Ter-Ovanesyan, Elena, Uttard, Alex, Xiao, Dongmei, Xu, Jian, Xu, Ling, Bergstrom, Donald A, Lowinger, Timothy B
• Format: Article
• Language: English
• Subjects: Animals; Antigens, Neoplasm - metabolism; Female; Humans; Immunoconjugates - pharmacology; Immunoconjugates - therapeutic use; Mice; Mice, SCID; Neoplasms - drug therapy; Oligopeptides - pharmacology; Oligopeptides - therapeutic use; Polymers - pharmacology; Polymers - therapeutic use
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-20-0183

Target selection for antibody-drug conjugates (ADC) frequently focuses on identifying antigens with differential expression in tumor and normal tissue, to mitigate the risk of on-target toxicity. However, this strategy restricts the possible target space. SLC34A2/NaPi2b is a sodium phosphate transporter expressed in a variety of human tumors including lung and ovarian carcinoma, as well as the normal tissues from which these tumors arise. Previous clinical trials with a NaPi2b targeting MMAE-ADCs have shown objective durable responses. However, the protein-based biomarker assay developed for use in that study was unable to discern a statistically significant relationship between NaPi2b protein expression and the probability of response. XMT-1536 is a NaPi2b targeting ADC comprised of a unique humanized antibody conjugated with 10-15 auristatin F- hydroxypropylamide (AF-HPA) payload molecules via the Dolaflexin platform. AF-HPA is a cell-permeable, antimitotic compound that is slowly metabolized intratumorally to an active, very low-permeable metabolite, auristatin F (AF), resulting in controlled bystander killing. We describe the preclinical and antitumor effects of XMT-1536 in models of ovarian and lung adenocarcinoma. Pharmacokinetic analysis showed approximately proportional increases in exposure in rat and monkey. Systemic free AF-HPA and AF concentrations were observed to be low in all animal species. Finally, we describe a unique IHC reagent, generated from a chimeric construct of the therapeutic antibody, that was used to derive a target expression and efficacy relationship in a series of ovarian primary xenograft cancer models.