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Abstract
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 in vitro and in vivo 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.
Highlights
Antibody-drug conjugates (ADCs) enable the tumor-targeted delivery of cytotoxic agents
We describe the preclinical in vitro and in vivo antitumor effects of XMT-1536 in models of ovarian and lung adenocarcinoma
CD30 is expressed in activated T and B-cells [3, 4]; brentuximab-vedotin, an antibody-drug conjugates (ADCs) targeting CD30, is approved for the treatment of tumors arising from these cell populations, including Hodgkin’s lymphoma and systemic anaplastic large cell lymphoma [2, 5, 6]
Summary
Antibody-drug conjugates (ADCs) enable the tumor-targeted delivery of cytotoxic agents. This therapeutic modality reduces the systemic toxicity associated with potent chemotherapeutic agents while enhancing the anti-tumor activity [1, 2]. CD30 is expressed in activated T and B-cells [3, 4]; brentuximab-vedotin, an ADC targeting CD30, is approved for the treatment of tumors arising from these cell populations, including Hodgkin’s lymphoma and systemic anaplastic large cell lymphoma [2, 5, 6]. Inotuzumab ozogamicin targets CD22, a B-cell lineage antigen, and is approved for B-cell precursor acute lymphoblastic leukemia [7]. Gentuzumab ozogamicin targets CD33, a myeloid lineage antigen, and is approved for acute myeloid leukemia [8]. Polatuzumab vedotin targets CD79b, an antigen expressed in B cells and B-cell lymphoma [9]
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