Points to consider regarding the use and implementation of virtual controls in nonclinical general toxicology studies.

The replacement of a proportion of concurrent controls by virtual controls in nonclinical safety studies has gained traction over the last few years. This is supported by foundational work, encouraged by regulators, and aligned with societal expectations regarding the use of animals in research. This paper provides an overview of the points to consider for any institution on the verge of implementing this concept, with emphasis given on database creation, risks, and discipline-specific perspectives.

Preclinical discovery and initial clinical data of WVT078, a BCMA × CD3 bispecific antibody.

B-cell maturation antigen (BCMA) is an ideal target in multiple myeloma (MM) due to highly specific expression in malignant plasma cells. BCMA-directed therapies including antibody drug conjugates, chimeric antigen receptor-T cells and bispecific antibodies (BsAbs) have shown high response rates in MM. WVT078 is an anti-BCMA× anti-CD3 BsAb that binds to BCMA with subnanomolar-affinity. It was selected based on potent T cell activation and anti-MM activity in preclinical models with favorable tolerability in cynomolgus monkey. In the ongoing first-in-human phase I dose-escalation study (NCT04123418), 33 patients received intravenous WVT078 once weekly at escalated dosing. At the active doses of 48-250 µg/kg tested to date (n = 26), the overall response rate (ORR) was 38.5% (90% CI: 22.6-56.4%) and the complete response rate (CRR, stringent complete response + complete response) was 11.5%, (90% CI: 3.2-27.2%). At the highest dose level tested, the ORR was 75% (3 of 4 patients). 26 (78.8%) patients reported at least one Grade ≥3 AE and 16 of these AEs were suspected to be drug related. 20 patients (60.6%) experienced cytokine release syndrome. WVT078 has an acceptable safety profile and shows preliminary evidence of clinical activity at doses tested to date.

The T-cell-dependent antibody response assay in nonclinical studies of pharmaceuticals and chemicals: study design, data analysis, interpretation.

The T-cell-dependent antibody response (TDAR) assay is a measure of immune function that is dependent upon the effectiveness of multiple immune processes, including antigen uptake and presentation, T cell help, B cell activation, and antibody production. It is used for risk and safety assessments, in conjunction with other toxicologic assessments, by the chemical and pharmaceutical industries, and research and regulatory agencies. It is also employed to evaluate investigational drug efficacy in animal pharmacology studies, provide evidence of biological impact in clinical trials, and evaluate immune function in patients with primary or secondary immunodeficiency diseases. Various immunization schemes, analytical methods, approaches to data analysis, and data interpretations are in use. This manuscript summarizes some recommended practices for the conduct and interpretation of the assay in animal studies.

Immunohistochemical characterization of estrogen and progesterone receptors in lymphoma of horses.

Immunohistochemical techniques were used to examine 29 cases of equine lymphoma for estrogen receptor (ER) and progesterone receptor (PR) expression. The lymphomas examined included T-cell-rich large B-cell lymphomas, B-cell neoplasms, and T-cell lymphomas. The individual cases were also classified according to the anatomic location of the tumors. One normal equine lymph node was also examined for ER and PR expression. All of the cases of equine lymphoma and the normal lymph node were negative for Er. A total of 16/29 (55%) PR-positive lymphomas were identified. Seven of the 12 (58%) T-cell-rich large B-cell lymphomas were positive, 7/11 (64%) B-cell tumors were positive, and 2/6 (33%) T-cell neoplasms were positive. Anatomically, 6/9 (66%) subcutaneous lymphomas were PR positive, 3/5 (60%) intrathoracic lymphomas were positive, 1/4 (25%) intra-abdominal lymphomas were positive, 2/5 (40%) intra-abdominal/intrathoracic lymphomas were positive, 1/2 (50%) upper airway lymphomas were positive, and 3/3 (100%) splenic lymphomas were positive. One case involving abdominal and thoracic tumors and leukemia was negative for PR expression. The normal lymph node contained a low percentage (1.9%) of PR-positive lymphocytes. The presence of PR in neoplastic equine lymphoid tissue indicates that these tumors may be responsive to serum progesterone. Also, identification of PR-positive cells in the normal lymph node suggests that PR may be constitutively expressed in normal equine lymphocytes. Further studies are needed to quantify PR levels in normal and malignant equine lymphoid tissue and to determine the usefulness of either progestin or antiprogestin drugs in the management of equine lymphoma.