Which risks did regulators probe for approved bispecifics?

“In vitro cytokine release studies using whole human blood from healthy donors showed only slight increases in cytokine levels.”

“No distribution studies were performed.”

“Increases in cytokines IL-2, IL-6, and INFγ were also observed following infusion with blinatumomab in chimpanzees, a finding consistent with the cytokine release syndrome observed in the clinical trial in patients with ALL.”

“The mean terminal half-lives in the tested species ranged from 1.5 to 8 hours, indicating rapid elimination of the drug.”

“Gpt resulted in the attenuation of cytokine release allowing higher doses to be administered in cynomolgus monkeys. Administration of a low-dose prior to administering higher doses (step-up dosing) also mitigated the dose-limiting cytokine response.”

“No dedicated studies have been performed to investigate the in vivo tissue distribution of glofitamab in animals, as per ICH S6(R1).”

“Increased cytokine levels were considered transient since they were mainly observed after the first dose but not after subsequent doses.”

“Protein binding and tissue distribution studies were not conducted for elranatamab in nonclinical species.”

“Dose-dependent increases in the plasma cytokines IL-2, IL-6, IL-8, IL-10, IL-15, IFN-γ, TNF-α, and MCP-1 were observed in all epcoritamab-treated groups after the first dose.”

“Epcoritamab displayed a clear pattern of target-mediated drug disposition, with faster clearance of drug at low doses compared with high doses.”

“The results of the assay indicated emicizumab has a low risk for eliciting cytokine release.”

“No studies to evaluate the distribution, metabolism, excretion or potential to cause pharmacokinetic interactions were conducted which is in line with the ICH S6 guideline (R1)”

“One animal had vascular injury-associated changes in the heart and lung that were consistent with secondary effects likely mediated by ADA-related immune complexes.”

“muS757 was detected in fetal serum at concentrations up to 30-times higher than maternal serum concentrations, indicating the potential for tarlatamab to cross the placenta.”

“Tebentafusp did not show evidence for increased release of 5 key cytokines in the presence of whole blood at < 1 nM.”

“Preclinical biodistribution studies demonstrate that tebentafusp is being retained in the melanoma tumor for a significantly longer timeframe compared to other non-target tissues, with a half-life of tumour retention of approximately 24 hours.”

“In vitro data show that catumaxomab can induce the production of pro-inflammatory cytokines (e.g. TNF-α, IL-6 and IL-2) in the presence of EpCAM-expressing tumour cells.”

“Tumour uptake of catumaxomab increased over the first 48 h and peaked at 15.7% ID/g; it then declined to 6.6% ID/g on Day 4.”

“Observed toxicities in GLP-study 14-1246 were largely attributed to a dose-dependent release of cytokines which occurred 2-6 hours post-dosing and returned to baseline values at 24 hours post-dose.”

“Vss-values were greater than estimated serum volume of cynomolgus monkeys, most likely due to specific binding of mosunetuzumab to its target cells.”

“the most severely impacted animals showed a dose-dependent induction of CRP that correlated with increased IL-2, IL-6, and MCP-1.”

“No unanticipated cross-reactivity of linvoseltamab was observed in either study.”

“Overall, based on the in vitro data on cytokine release there is a limited value in translating these results to a clinical setting for assessment of CRS.”

“As expected, based on the known expression of CD20 by B cells and CD3 by T cells, REGN1979-Bio stained the membrane and/or cytoplasm of mononuclear leukocytes in both lymphoid”

“The greatest stimulatory effect of catumaxomab was seen for TNF-α and IL-6, and a smaller stimulatory effect was seen for IL-2.”

“Catumaxomab localised to the tumour. The time-activity course for both catumaxomab and a control antibody without tumour specificity in non-target organs was similar.”

“In an in vitro assay using human blood, the cytokine release profile for amivantamab was similar to that of the negative control, indicating a low risk for cytokine release syndrome.”

“Conventional distribution, metabolism, and excretion studies were not conducted for amivantamab since it is a immunoglobulin G (IgG)-based monoclonal antibody (mAb) with a molecular weight of approximately 148,000 Daltons (kD).”

“Antidrug antibodies (ADAs) were observed in 10/12 JNJ-64024701-treated monkeys, and ADA-positive animals exhibited decreased JNJ-64024701 exposure following repeated doses.”

“Traditional distribution studies were not conducted for talquetamab, which is an antibody with a molecular weight of 147 kDa.”

“Antidrug antibodies (ADAs) were detected in 21/30 teclistamab-treated animals, and seven of these animals exhibited lower teclistamab exposure after dosing on Day 22 or Day 29.”

“Due to its molecular size, teclistamab is expected to be primarily confined to the vascular space with only limited distribution to the extracellular space, which is typical for IgG-based mAbs.”

“These data support that the ocular findings were primarily related to ADA formation and not a direct pro-inflammatory effect of faricimab.”

“Bioavailability was 2.2% in the rabbit and 13% in the cynomolgus monkey.”

“Zanidatamab displayed low immunogenic potential in a functional human PBMC proliferation assay.”

“In vivo tissue distribution studies have not been performed with zanidatamab.”