Determination of starting dose of the T cell-redirecting bispecific antibody ERY974 targeting glypican-3 in first-in-human clinical trial.

Currently, ERY974, a humanized IgG4 bispecific T cell-redirecting antibody recognizing glypican-3 and CD3, is in phase I clinical trials. After a first-in-human clinical trial of an anti-CD28 agonist monoclonal antibody resulting in severe life-threatening adverse events, the minimal anticipated biological effect level approach has been considered for determining the first-in-human dose of high-risk drugs. Accordingly, we aimed to determine the first-in-human dose of ERY974 using both the minimal anticipated biological effect level and no observed adverse effect level approaches.

An anti-glypican 3/CD3 bispecific T cell-redirecting antibody for treatment of solid tumors.

Cancer care is being revolutionized by immunotherapies such as immune checkpoint inhibitors, engineered T cell transfer, and cell vaccines. The bispecific T cell-redirecting antibody (TRAB) is one such promising immunotherapy, which can redirect T cells to tumor cells by engaging CD3 on a T cell and an antigen on a tumor cell. Because T cells can be redirected to tumor cells regardless of the specificity of T cell receptors, TRAB is considered efficacious for less immunogenic tumors lacking enough neoantigens.

Effects of SA237, a humanized anti-interleukin-6 receptor monoclonal antibody, on pre- and postnatal development in cynomolgus monkey.

Background: SA237 is a humanized anti-interleukin-6 receptor (IL-6R) monoclonal antibody in which the constant and variable regions have been engineered for a longer plasma half-life. According to literature, blocking of IL-6 related functions could have an influence on pregnancy sustainment, development of the immune system, and brain growth.

Methods: SA237 effects on dams, embryo-fetal development, parturition and postnatal development were investigated in an enhanced pre- and postnatal development study, in which SA237 was subcutaneously administered to pregnant cynomolgus monkeys at dose levels of 2 or 50 mg/kg once weekly from gestation day 20 until parturition.

Safety and immunotoxicity assessment of immunomodulatory monoclonal antibodies.

Most therapeutic monoclonal antibodies (mAbs) licensed for human use or in clinical development are indicated for treatment of patients with cancer and inflammatory/autoimmune disease and as such, are designed to directly interact with the immune system. A major hurdle for the development and early clinical investigation of many of these immunomodulatory mAbs is their inherent risk for adverse immune-mediated drug reactions in humans such as infusion reactions, cytokine storms, immunosuppression and autoimmunity. A thorough understanding of the immunopharmacology of a mAb in humans and animals is required to both anticipate the clinical risk of adverse immunotoxicological events and to select a safe starting dose for first-in-human (FIH) clinical studies.

Immunotoxicity testing in nonhuman primates.

Biological relevance is generally the major justification for using nonhuman primates (NHP) during preclinical safety assessment. This holds particularly true for the evaluation of biopharmaceuticals with NHP often being the species of choice. For safety assessment of small molecules, NHP are used in case of a higher degree of metabolic similarity, to detect the highly specific immunotoxic side effects and to discriminate toxicity from efficacy of immunomodulatory drugs.

Loss of S100A9 (MRP14) results in reduced interleukin-8-induced CD11b surface expression, a polarized microfilament system, and diminished responsiveness to chemoattractants in vitro.

The S100A9 (MRP14) protein is abundantly expressed in myeloid cells and has been associated with various inflammatory diseases. The S100A9-deficient mice described here were viable, fertile, and generally of healthy appearance. The myelopoietic potential of the S100A9-null bone marrow was normal.

Only the soluble form of the scavenger receptor CD163 acts inhibitory on phorbol ester-activated T-lymphocytes, whereas membrane-bound protein has no effect.

The extracellular moiety of the hemoglobin/haptoglobin scavenger receptor CD163 (RM3/1 antigen) can be shed from monocytes and is a normal plasma component. We found that in a dose-dependent manner soluble CD163 induces a decrease in CD69 expression, a reduced [(3)H]thymidine uptake and a down-regulated matrix metalloproteinase-9 RNA expression in phorbol myristate acetate-stimulated T-cells. Co-culturing T-cells on transgenic fibroblasts, expressing membrane-bound CD163, yielded no differences compared to culture on non-transfected cells.

Adaptation of primate cell-adapted hepatitis A virus strain HM175 to growth in guinea pig cells is independent of mutations in the 5' nontranslated region.

Previous studies of hepatitis A virus (HAV) genotypes after adaptation of wild-type virus to growth in cell cultures of primate origin identified determinants for growth in cell culture in the viral 2B and 2C protein-coding regions of the genome and demonstrated that an increased growth efficiency in a particular cell line was achieved by subsequent mutations in the 5' nontranslated region (5'NTR). The results reported in this study demonstrate that the passage of HAV adapted to primate BS-C-1 cells in guinea pig cells resulted in increased growth efficiency in the rodent cells and decreased growth efficiency in BS-C-1 cells. This adaptation occurred without mutation in the 5'NTR, but the viral 2B and 2C proteins seem to play a role during adaptation to the new environment, as one mutation occurred in each protein.