theralizumab (TAB08)

Strong HUVEC-activation and reduced viability was observed upon treatment with IL-1β, tumor necrosis factor (TNF)-α, a TGN1412-induced cytokine cocktail (SNTGN1412), thrombin, and lipopolysaccharide (LPS)...Moreover, we observed that the interplay with immune cells is critical to enhance relative HUVEC-permeability, which however depended on the stimulus applied suggesting different mechanisms of immune-mediated VL. A better understanding of VL will uncover potential treatment-targets for patients suffering from VL and help to improve safety-assessment of leakage-associated immunotherapies.

We developed a bispecific CD19-targeted CD28 agonist (RG6333, CD19-CD28) to enhance the efficacy of glofitamab and similar TCBs by delivering signal 2 to tumor-infiltrating T cells. CD19-CD28 distinguishes itself from the superagonistic antibody TGN1412, as its activity requires the simultaneous presence of a TCR signal and CD19 target binding...Our findings highlight CD19-CD28 as a safe and highly efficacious off-the-shelf combination partner for glofitamab, similar TCBs, and other costimulatory agonists. CD19-CD28 is currently in a Phase 1 clinical trial in combination with glofitamab.

However, the development of CD28-targeting therapies ceased after TeGenero's Phase 1 trial in 2006 evaluating a superagonistic anti-CD28 antibody (TGN1412) resulted in severe life-threatening side effects...In an in vitro activity assay using human PBMCs, the combination of E1P2 with CD3 bispecific antibodies enhanced tumor cell killing and T-cell proliferation. Collectively, these data demonstrate the therapeutic potential of E1P2 to improve the activity of T-cell receptor/CD3 activating constructs in targeted immunotherapeutic approaches against cancer or infectious diseases.

The superagonistic monoclonal anti-human CD28 antibody (IgG4κ) TGN1412 was used as comparator. Activity is maintained while it allows well tailorable dose response with reduced cytokine release. Compounds are currently in extensive pre-clinical assessment 999

In contrast, TGN1412, a CD28 superagonist antibody, induced strong T cell activation, proliferation and cytokine secretion in vitro and in huNSG. Scheduling studies with glofitamab and RG6333 in huNSG suggest a safe and potent treatment regimen by using Gazyva pre-treatment followed by a staggered infusion of glofitmab and RG6333 applying an interval of three days at the first treatment cycle...Interestingly, the alternation of RG6333 with an alternative 4-1BB costimulatory agent (RG6076; CD19-4-1BBL) completely prevented tumor relapse during glofitamab treatment for more than 120 days when RG6333 was given for the first treatment cycles followed by RG6076 at later cycles...Optimal scheduling including alternation of costimulatory bispecific antibodies suggest a powerful off-the-shelf T cell redirection approach as an alternative to CAR-T cell therapies. RG6333 is currently in a phase I, open-label, dose-escalation study in combination with glofitamab (NCT05219513).

Patients received 4-6 (3 week)cycles of paclitaxel/carboplatin plus TAB008 or Avastin® at 15mg/kg intravenously, followed by 7.5mg/kg maintenance dose until disease progression, unacceptable toxicity, or death. TAB008 is similar to bevacizumab(Avastin®) in terms of efficacy, safety, and pharmacokinetic parameters. TOT BIOPHARM.

Patients received 4-6 (3 week)cycles of paclitaxel/carboplatin plus TAB008 or Avastin® at 15mg/kg intravenously, followed by 7.5mg/kg maintenance dose until disease progression, unacceptable toxicity, or death. Legal entity responsible for the study: TOT BIOPHARM. Funding: TOT BIOPHARM.

Patients received 4-6 (3 week)cycles of paclitaxel/carboplatin plus TAB008 or Avastin® at 15mg/kg intravenously, followed by 7.5mg/kg maintenance dose until disease progression, unacceptable toxicity, or death. TAB008 is similar to bevacizumab(Avastin®) in terms of efficacy, safety, and pharmacokinetic parameters. TOT BIOPHARM.

Patient started atezolizumab, carboplatin, and etoposide on day 1 of admission... Cytokine release syndrome is classically associated with immune therapy, particularly anti-CD3(OKT3), anti-CD52(alemtuzumab), anti-CD20(rituximab), and anti-CD28(TGN1412). Rarely has it been seen with checkpoint inhibitor therapy although there have been case reports associated with nivolumab... Awareness of specific markers and overlap syndromes may alert clinicians that interventions to treat CRS are necessary in addition to treatment addressing IrAE. Tocilizumab, an anti-IL-6 receptor antagonist is an FDA-approved treatment for CRS and may be indicated in patients with overlap syndromes.