A BCMA/CD16A bispecific innate cell engager for the treatment of multiple myeloma.

Despite the recent progress, multiple myeloma (MM) is still essentially incurable and there is a need for additional effective treatments with good tolerability. RO7297089 is a novel bispecific BCMA/CD16A-directed innate cell engager (ICE®) designed to induce BCMA+ MM cell lysis through high affinity binding of CD16A and retargeting of NK cell cytotoxicity and macrophage phagocytosis. Unlike conventional antibodies approved in MM, RO7297089 selectively targets CD16A with no binding of other Fcγ receptors, including CD16B on neutrophils, and irrespective of 158V/F polymorphism, and its activity is less affected by competing IgG suggesting activity in the presence of M-protein. Structural analysis revealed this is due to selective interaction with a single residue (Y140) uniquely present in CD16A opposite the Fc binding site. RO7297089 induced tumor cell killing more potently than conventional antibodies (wild-type and Fc-enhanced) and induced lysis of BCMA+ cells at very low effector-to-target ratios. Preclinical toxicology data suggested a favorable safety profile as in vitro cytokine release was minimal and no RO7297089-related mortalities or adverse events were observed in cynomolgus monkeys. These data suggest good tolerability and the potential of RO7297089 to be a novel effective treatment of MM patients.

Prevalence Study of PD-L1 SP142 Assay in Metastatic Triple-negative Breast Cancer.

Metastatic triple-negative breast cancer (mTNBC) is the most aggressive breast cancer subtype. Programmed death ligand 1 (PD-L1) on immune cells (IC) using the VENTANA SP142 assay is linked to improved clinical outcome in atezolizumab plus nab-paclitaxel-treated patients with mTNBC in the IMpassion130 study. The goal of the current study was to evaluate prevalence of VENTANA SP142 PD-L1 assay by anatomic location in 670 histologically confirmed TNBC cases from subjects with metastatic disease screened for the phase 1 study PCD4989g (NCT01375842). PD-L1 immunohistochemistry was centrally tested on tumor cells (TC) and on tumor infiltrating IC, following manufacturer's instructions. At a 1% cutoff, tumor PD-L1 was more prevalent in IC than TC: 46% were PD-L1 IC+/TC-, 3% were PD-L1 IC-/TC+, and 10% were PD-L1 IC+/TC+. PD-L1 IC and TC immunostaining correlated with CD274 RNA expression, as assessed by fluidigm. Analyses of anatomic locations suggest that prevalence of PD-L1 IC+ was highest in lymph nodes (65.0%), lowest in liver metastases (26.9%), while breast tissue was intermediate (57.1%). Matched paired samples from the same subject collected synchronously or asynchronously showed a PD-L1 IC status agreement of 80% (8/10) and 75% (15/20), respectively. Our results suggest that the anatomic location of metastases and time of collection may influence the detection of PD-L1.

Membrane-Proximal Epitope Facilitates Efficient T Cell Synapse Formation by Anti-FcRH5/CD3 and Is a Requirement for Myeloma Cell Killing.

The anti-FcRH5/CD3 T cell-dependent bispecific antibody (TDB) targets the B cell lineage marker FcRH5 expressed in multiple myeloma (MM) tumor cells. We demonstrate that TDBs trigger T cell receptor activation by inducing target clustering and exclusion of CD45 phosphatase from the synapse. The dimensions of the target molecule play a key role in the efficiency of the synapse formation. The anti-FcRH5/CD3 TDB kills human plasma cells and patient-derived myeloma cells at picomolar concentrations and results in complete depletion of B cells and bone marrow plasma cells in cynomolgus monkeys. These data demonstrate the potential for the anti-FcRH5/CD3 TDB, alone or in combination with inhibition of PD-1/PD-L1 signaling, in the treatment of MM and other B cell malignancies.