NAV-001, a high-efficacy antibody-drug conjugate targeting mesothelin with improved delivery of a potent payload by counteracting MUC16/CA125 inhibitory effects

Abstract

Subsets of tumor-produced cell surface and secreted proteins can bind to IgG1 type antibodies and suppress their immune-effector activities. As they affect antibody and complement-mediated immunity, we call these proteins humoral immuno-oncology (HIO) factors. Antibody-drug conjugates (ADCs) use antibody targeting to bind cell surface antigens, internalize into the cell, then kill target cells upon liberation of the cytotoxic payload. Binding of the ADC antibody component by a HIO factor may potentially hamper ADC efficacy due to reduced internalization. To determine the potential effects of HIO factor ADC suppression, we evaluated the efficacy of a HIO-refractory, mesothelin-directed ADC (NAV-001) and a HIO-bound, mesothelin-directed ADC (SS1). The HIO factor MUC16/CA125 binding to SS1 ADC was shown to have a negative effect on internalization and tumor cell killing. The MUC16/CA125 refractory NAV-001 ADC was shown to have robust killing of MUC16/CA125 expressing and non-expressing tumor cells in vitro and in vivo at single, sub-mg/kg dosing. Moreover, NAV-001-PNU, which contains the PNU-159682 topoisomerase II inhibitor, demonstrated good stability in vitro and in vivo as well as robust bystander activity of resident cells while maintaining a tolerable safety profile in vivo. Single-dose NAV-001-PNU demonstrated robust tumor regression of a number of patient-derived xenografts from different tumor types regardless of MUC16/CA125 expression. These findings suggest that identification of HIO-refractory antibodies to be used in ADC format may improve therapeutic efficacy as observed by NAV-001 and warrants NAV-001-PNU’s advancement to human clinical trials as a monotherapy to treat mesothelin-positive cancers.

NAV‐003, a bispecific antibody targeting a unique mesothelin epitope and CD3ε with improved cytotoxicity against humoral immunosuppressed tumors

“…MUC1 has been found to be overexpressed by several carcinomas and its presence has been associated with immunosuppression of ADCC; however, its mechanism of immune effector suppression has not been elucidated [18]. The huYP218 antibody, which constitutes NAV-003's anti-MSLN binding arm, was previously reported to weakly bind MUC16/CA125 [19]. Here, we confirm that NAV-003 poorly binds to MUC16/CA125 HIO factor (Fig.…”

MUC16: clinical targets with great potential

“…PankoMab-GEX has excellent preclinical antitumor activity and has been tested in Phase I and Phase IIb clinical trials (ClinicalTrials.gov Identifier: NCT01222624 and ClinicalTrials.gov Identifier: NCT01899599). Drugs that target MUC16 glycosylation sites also reduce off-target effects, For example, a HIO-refractory, mesothelin-directed ADC (NAV-001) [ 75 ] can effectively block the interaction between the intermediate skin protein of tumor cells and CA125 by identifying the glycosylation site of the CA125 binding domain and monoclonal antibody (mAb) AR9.6 and its humanized variant huAR9.6 bind MUC16 to the ErbB (EGF) receptor on the surface of cancer cells by binding to SEA domain 5(a conformational epitope influenced by O -glycoylation) on MUC16 to disrupt the binding of MUC16 to the ERbB (EGF) receptor [ 55 , 76 ]. Both of them can effectively inhibit the growth of tumor cells, but at present only stay in pre-clinical experiments, and the relevant efficacy needs to be further verified in clinical trials.…”

MUC1 and MUC16: critical for immune modulation in cancer therapeutics

“…Concurrently, regarding MUC16, Nicolaides et al. focused on the role of MUC16 (CA125) ADCs, discovering that a specific anti-MUC16 ADC (NAV-001) is significantly effective in eliminating tumor cells, highlighting MUC16’s potential as a therapeutic target ( 141 ). Moreover, Garg et al.…”