BackgroundMultiple myeloma is a malignancy characterized by the expansion of a plasma cell clone that localizes to the human bone marrow. Myeloma cells and bone marrow stromal cells produce soluble factors that promote the survival and progression of multiple myeloma. Interleukin 16 (IL-16) is involved in regulating the migration and proliferation of normal leukocytes. However, the role of IL-16 in human cancers, including multiple myeloma, is unclear.
Abstract BACKGROUND AND OBJECTIVES: The majority of patients with multiple myeloma (MM) will eventually relapse and succumb to their disease even after high dose chemotherapy and autologous stem cell transplantation, possibly due to the persistence of BM-residing myeloma stem cells. Therefore, new treatment strategies incorporating new therapeutic targets - ideally to be expressed by the bulk of end-stage myeloma cells and their dormant progenitors - are needed to improve the outcome of myeloma patients. DESIGN AND METHODS: We screened myeloma cell lines for the presence of a large number of immunoreceptors and verified expression of potential target molecules on cell lines and patient samples. The function of the respective proteins was evaluated using gene knockdown and their potential as targets for antibody therapies was investigated using in vitro cytotoxicity assays. RESULTS: Of all immunoreceptors analyzed, SLAM family member CD229 showed the strongest expression and was also found on myeloma precursors. Primary myeloma cells of myeloma patients uniformly evidenced CD229 surface expression while the molecule was absent from most healthy human tissues. Flow cytometric analysis of CD229 expression facilitated the detection of myeloma cells in the bone marrow. CD229 seemed to promote the survival of myeloma cells while CD229 silencing increased their susceptibility towards chemotherapy. Importantly, targeting CD229 with a monoclonal antibody resulted in specific lysis of the tumor cells. CONCLUSIONS: These results suggest that CD229 might represent an attractive diagnostic and therapeutic target for the treatment of MM. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2450.
Abstract Objectives This study reports long‐term outcomes from the open‐label extension (OLE) period of the Phase I/II COMPOSER trial (NCT03157635) that evaluated crovalimab in patients with paroxysmal nocturnal haemoglobinuria, who were treatment‐naive or switched from eculizumab at enrolment. Methods COMPOSER consists of four sequential parts followed by the OLE. The primary OLE objective was to assess long‐term crovalimab safety, with a secondary objective to assess crovalimab pharmacokinetics and pharmacodynamics. Exploratory efficacy endpoints included change in lactate dehydrogenase (LDH), transfusion avoidance, haemoglobin stabilisation and breakthrough haemolysis (BTH). Results A total 43 of 44 patients entered the OLE after completing the primary treatment period. Overall, 14 of 44 (32%) experienced treatment‐related adverse events. Steady state exposure levels of crovalimab and terminal complement inhibition were maintained over the OLE. During the OLE, mean normalised LDH was generally maintained at ≤1.5× upper limit of normal, transfusion avoidance was achieved in 83%–92% of patients and haemoglobin stabilisation was reached in 79%–88% of patients across each 24‐week interval. Five BTH events occurred with none leading to withdrawal. Conclusions Over a 3‐year median treatment duration, crovalimab was well tolerated and sustained C5 inhibition was achieved. Intravascular haemolysis control, haemoglobin stabilisation and transfusion avoidance were maintained, signifying long‐term crovalimab efficacy.
