TREM1 activation of myeloid cells promotes antitumor immunity.

Myeloid cells in the tumor microenvironment (TME) can exist in immunosuppressive and immunostimulatory states that impede or promote antitumor immunity, respectively. Blocking suppressive myeloid cells or increasing stimulatory cells to enhance antitumor immune responses is an area of interest for therapeutic intervention. Triggering receptor expressed on myeloid cells-1 (TREM1) is a proinflammatory receptor that amplifies immune responses.

Targeting TREM2 on tumor-associated macrophages enhances immunotherapy.

Converting checkpoint inhibitor (CPI)-resistant individuals to being responsive requires identifying suppressive mechanisms. We identify TREM2 tumor-associated macrophages (TAMs) as being correlated with exhausted CD8 tumor-infiltrating lymphocytes (TILs) in mouse syngeneic tumor models and human solid tumors of multiple histological types. Fc domain-enhanced anti-TREM2 monoclonal antibody (mAb) therapy promotes anti-tumor immunity by elimination and modulation of TAM populations, which leads to enhanced CD8 TIL infiltration and effector function.

Blockade of nonhormonal fibroblast growth factors by FP-1039 inhibits growth of multiple types of cancer.

The fibroblast growth factor (FGF) pathway promotes tumor growth and angiogenesis in many solid tumors. Although there has long been interest in FGF pathway inhibitors, development has been complicated: An effective FGF inhibitor must block the activity of multiple mitogenic FGF ligands but must spare the metabolic hormone FGFs (FGF-19, FGF-21, and FGF-23) to avoid unacceptable toxicity. To achieve these design requirements, we engineered a soluble FGF receptor 1 Fc fusion protein, FP-1039.

Chronic administration of belimumab, a BLyS antagonist, decreases tissue and peripheral blood B-lymphocyte populations in cynomolgus monkeys: pharmacokinetic, pharmacodynamic, and toxicologic effects.

The tolerability, pharmacodynamic effects, and pharmacokinetics of belimumab (LymphoStat-B) were evaluated in cynomolgus monkeys. Belimumab is a fully human IgG1lambda antibody directed against B-lymphocyte stimulator (BLyS) protein. BLyS is a TNF family member that supports B-lymphocyte maturation and survival and has been implicated in the pathogenesis of autoimmune diseases and B-lymphocyte malignancies.

BLyS--an essential survival factor for B cells: basic biology, links to pathology and therapeutic target.

A paradigm shift in our understanding of autoimmune disease pathology is underway; B cells are now considered to play a central role in disease pathogenesis. Targeting B cells may prove to be an effective route for the development of novel therapeutics. BLyS, a member of the TNF family of cytokines, is an essential survival factor for B cells.

B lymphocyte stimulator overexpression in patients with systemic lupus erythematosus: longitudinal observations.

Objective: To assess the overexpression of B lymphocyte stimulator (BLyS) over time in patients with systemic lupus erythematosus (SLE).

Methods: Sixty-eight SLE patients were followed up longitudinally for a median 369 days. At each physician encounter, disease activity was assessed by the Systemic Lupus Erythematosus Disease Activity Index, and blood was collected for determination of the serum BLyS level, blood BLyS messenger RNA (mRNA) level, and cell surface BLyS expression.

Generation and characterization of LymphoStat-B, a human monoclonal antibody that antagonizes the bioactivities of B lymphocyte stimulator.

Objective: To identify and characterize a fully human antibody directed against B lymphocyte stimulator (BLyS), a tumor necrosis factor-related cytokine that plays a critical role in the regulation of B cell maturation and development. Elevated levels of BLyS have been implicated in the pathogenesis of autoimmune diseases.

Methods: A human phage display library was screened for antibodies against human BLyS.

BLyS and APRIL form biologically active heterotrimers that are expressed in patients with systemic immune-based rheumatic diseases.

BLyS and APRIL are two members of the TNF superfamily that are secreted by activated myeloid cells and have costimulatory activity on B cells. BLyS and APRIL share two receptors, TACI and BCMA, whereas a third receptor, BAFF-R, specifically binds BLyS. Both BLyS and APRIL have been described as homotrimeric molecules, a feature common to members of the TNF superfamily.