- |||||||||| theralizumab (TAB08) / TheraMab
Conditionally active CD28xVISTA bispecific antibodies induce myeloid-driven tumor-specific T-cell co-stimulation for improved cancer immunotherapy (Section 3) - Mar 5, 2024 - Abstract #AACR2024AACR_8268;
This approach, which bypasses the need for tumor-associated antigens (TAAs) required by other CD28xTAA bispecifics in development, suggests a potentially safer alternative for T-cell engagement and stimulation. Moreover, our novel myeloid-directed TME-selective co-stimulation strategy with a CD28xVISTA bsAb may broaden the potential for T-cell engagement approaches in solid tumors by enabling rational combinations with existing CD3xTAA T-cell engagers without competing for the same target.
- |||||||||| theralizumab (TAB08) / TheraMab
CD28 humanized mouse model for efficacy and safety assessment of CD28-targeting therapies (Section 3) - Mar 5, 2024 - Abstract #AACR2024AACR_8266;
Furthermore, TGN1412 administration in CD28 mice induces cytokine release, and a slightly body weight loss, but no major change in body temperature...A non-conserved amino acid variant regulates differential signalling between human and mouse CD28. Nat Commun 2018; 9:1-16
- |||||||||| theralizumab (TAB08) / TheraMab
Discovery of agonist CD28-specific single domain antibodies from alpaca (Section 42) - Mar 5, 2024 - Abstract #AACR2024AACR_3799;
Development of superagonistic CD28-targeting antibody has been paused after TeGenero's TGN1412 Phase 1 trial in 2006 due to life-threatening cytokine release syndrome...All purified VHH-Fc showed sub-nanomolar affinity by ELISA and bind to primary T cells by flow cytometry. Three VHH-Fc induced IL-2 production in a primary T cells activation assay only when cross-linked and in the presence of CD3 co-stimulation and are suitable for further bispecific T cell engager development.
- |||||||||| theralizumab (TAB08) / TheraMab
CAR T CELLS TARGETING CD28 SHOW PRECLINICAL ACTIVITY AGAINST T-ALl (CLYDE) - Feb 14, 2024 - Abstract #EBMT2024EBMT_1073;
Next, we designed 20 CAR molecules against CD28 based on five publicly available scFvs and identified two lead molecules by in vitro testing (FIG_1I&J) termed 28CAR_2 (scFv: TGN1412) and 28CAR_14 (scFv: CD28.3)... Taken together, our data highlight CD28 CAR T-cells as a novel synthetic immunotherapy against T-ALL and beyond.
- |||||||||| theralizumab (TAB08) / TheraMab
CAR T CELLS TARGETING CD28 SHOW PRECLINICAL ACTIVITY AGAINST T-ALl (ePoster area) - Feb 14, 2024 - Abstract #EBMT2024EBMT_1072;
Next, we designed 20 CAR molecules against CD28 based on five publicly available scFvs and identified two lead molecules by in vitro testing (FIG_1I&J) termed 28CAR_2 (scFv: TGN1412) and 28CAR_14 (scFv: CD28.3)... Taken together, our data highlight CD28 CAR T-cells as a novel synthetic immunotherapy against T-ALL and beyond.
- |||||||||| theralizumab (TAB08) / TheraMab
Journal: Using Reference Reagents to Confirm Robustness of Cytokine Release Assays for the Prediction of Monoclonal Antibody Safety. (Pubmed Central) - Oct 2, 2023
However, different labs using different control antibodies can threaten the harmonization of CRAs, and clinically relevant controls (such as TGN1412) can be difficult to source, which can lead to less accurate or reliable results or data which are difficult to compare between laboratories...Each antibody is provided with an isotype-matched negative control antibody. This panel of reference reagents has previously been shown to have good inter-lab reproducibility and are suitable controls to increase the confidence and robustness of safety data from a variety of CRA platforms.
- |||||||||| glofitamab (RG6026) / Roche, RG6333 / Roche
RG6333 (CD19-CD28), a CD19-Targeted Affinity-Optimized CD28 Bispecific Antibody, Enhances and Prolongs the Anti-Tumor Activity of Glofitamab (CD20-TCB) in Preclinical Models (ENMCC - Hall D) - Nov 4, 2022 - Abstract #ASH2022ASH_2194;
P1
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).
- |||||||||| A Bifunctional Tumor Activated Immunomodulator (TRACIr) Targeting PD-L1 And CD28 Is a Potent Enhancer of T Cell-Mediated Anti-Tumor Activity (Hall C) - Oct 6, 2022 - Abstract #SITC2022SITC_1630;
However, the first phase 1 clinical trial of the CD28 agonistic antibody TGN1412 failed due to an unexpected and rapid systemic proinflammatory cytokine response...PD-L1 blocking activity was comparable with atezolizumab, avelumab, nivolumab, and pembrolizumab...Finally, TRACIr was well tolerated in NHPs at high doses and exhibited half-life extended pharmacokinetics. Conclusions Preclinical activity and safety profiles of PDL1xCD28 TRACIr support its further development as an attractive bifunctional T cell modulator.
- |||||||||| theralizumab (TAB08) / TheraMab
A novel fully human CD28 antibody that cross-reacts with CTLA-4 and mouse CD28 for potential applications in cancer immunotherapy (Hall C) - Oct 6, 2022 - Abstract #SITC2022SITC_1382;
Conclusions VE19ZH is a promising module for cancer immunotherapy with unique properties: (i) Fully human mAb for minimal immunogenicity (ii) Potent co-stimulator for full T cell activation (iii) Conventional agonist of CD28 and not super-agonistic like TGN1412 (iv) cross reacts with mouse CD28 for better assessment in immunocompetent mouse models (v) Binds to human CTLA-4 for potential checkpoint inhibition. The potential of VE19ZH to boost T cell response via CD28 activation and CTLA-4 blockade is currently being investigated in vitro and in vivo.
- |||||||||| Darzalex (daratumumab) / J&J, CYT-338 / Cytovia Therap, theralizumab (TAB08) / TheraMab
NOVEL MULTIFUNCTIONAL TETRAVALENT CD38 NKP46 FLEX-NK ENGAGERS ACTIVELY TARGET AND KILL MULTIPLE MYELOMA CELLS () - May 13, 2022 - Abstract #EHA2022EHA_1925;
Cytokine release assessment of CYT-338 in the human PBMC assay showed no evidence of cytokine release while high levels of cytokine release was observed with daratumumab, anti-CD28 (TGN1412) and CD3 antibody controls. Conclusion These results suggest that the CYT-338 engager has a favorable NK cell engager profile for targeting CD38 expressing multiple myeloma distinct from daratumumab.
- |||||||||| theralizumab (TAB08) / TheraMab
A humanized mouse model to evaluate the systemic adverse effects of cytokine release syndrome induced by immunoactivating drugs () - May 9, 2022 - Abstract #CIMT2022CIMT_238;
The lack of predictive preclinical models to evaluate antibodymediated adverse effects can lead to clinical failures, such as TGN1412, a humanized anti-CD28 monoclonal antibody that caused life-threatening cytokine release syndrome (CRS) during the firstin-man trial...We have demonstrated that the novel mouse model using PBMC-humanized NSG™ or derivative strains can successfully detect CRS induced by immunoactivating antibodies in a dose- and timedependent manner. Our data support that the PBMC humanized mouse model for CRS assessment is a valuable tool to assess in vivo safety of experimental human immunoregulatory therapies, including immune checkpoint inhibitors, CAR T, and bispecific antibodies.
- |||||||||| theralizumab (TAB08) / TheraMab
Tumor-targeted CD28 bispecific POWERbodyTM for safe and synergistic T cell-mediated immunotherapy (Section 38) - Mar 9, 2022 - Abstract #AACR2022AACR_4819;
Targeting CD28 for systemic T cell activation caused severe cytokine storm and multiorgan failure in an anti-CD28 antibody TGN1412 phase 1 trial...When combined with TAA×CD3 TCEs and/or checkpoint inhibitors, they show strong synergistic T cell-mediated antitumor responses with robust safety profiles. Taken together, our tumor specific CD28 bispecific POWERbody TCEs exhibit enormous potential to fulfill the promises of safe and durable T cell-mediated immunotherapies when combined with CD3 bispecific POWERbody TCEs and/or checkpoint inhibitors.
- |||||||||| theralizumab (TAB08) / TheraMab
A novel, rapid, sensitive, and reproducible in vivo platform to assess efficacy and toxicity of bispecific antibodies (Section 37) - Mar 9, 2022 - Abstract #AACR2022AACR_4138;
The platform was validated using an anti-CD28 superagonist (TGN1412), which none of the pre-clinical in vitro assays and in vivo studies, including non-human primates, executed before clinical trials were able to predict the observed clinical toxicities...This model will also help to optimize the therapeutic drug dose range to improve the safety profile of BiTE and other immune-oncology drugs. We believe this platform will greatly benefit not only the scientific community but potentially cancer patients as well.
- |||||||||| theralizumab (TAB08) / TheraMab
Trial completion, Enrollment change, Metastases: Dose Escalation Study of TAB08 in Patients With Advanced Solid Neoplasms (clinicaltrials.gov) - Oct 6, 2021
P1b, N=12, Completed,
We believe this platform will greatly benefit not only the scientific community but potentially cancer patients as well. Recruiting --> Completed | N=38 --> 12
- |||||||||| Campath (alemtuzumab) / Sanofi, Erbitux (cetuximab) / Eli Lilly, EMD Serono
Journal: The blood endothelial cell chamber - An innovative system to study immune responses in drug development. (Pubmed Central) - May 20, 2021
In contrast, bacterial endotoxin demonstrated a clear innate cytokine response, defined by TNFα, IL-6 and IL-1β release, accompanied with a strong recruitment of CD14CD16 cells. Therefore, the blood endothelial cell chamber model is presented as a valuable in vitro tool to investigate therapeutic monoclonal antibodies with respect to cytokine release and vascular immune cell recruitment.
- |||||||||| BIA 10 2474 / Eisai, theralizumab (TAB08) / TheraMab
P1 data, Review, Journal: First-in-human dose: current status review for better future perspectives. (Pubmed Central) - May 13, 2021
Early phase clinical trials are basically foundation stones on which lies the entire onus of the later stages of development. Deciding FIH dose is a crucial step that necessitates the incorporation of detailed data from the preclinical stages and application of the most conservative approach for the safety/benefit of the volunteers in these studies.
- |||||||||| theralizumab (TAB08) / TheraMab
Review, Journal: Regulatory and strategic considerations for addressing immunogenicity and related responses in biopharmaceutical development programs. (Pubmed Central) - May 6, 2021
Anti-drug antibodies can impact the safety and efficacy of drug products, and related immune responses, like the cytokine release syndrome that occurred in the infamous TGN-1412 clinical trial, can be challenging to predict with nonclinical models...This process begins at the discovery stage with the application of "quality by design," continues into the clinic with the development of quality assays and management strategies, and culminates in the effective presentation of this information in regulatory documents. This review provides an overview of some of the key strategic and regulatory considerations for biotherapeutics as they pertain to immunogenicity and related responses.
- |||||||||| theralizumab (TAB08) / TheraMab
Journal, Cytokine storm: Myelopoiesis of acute inflammation: lessons from TGN1412-induced cytokine storm. (Pubmed Central) - Mar 31, 2021
Granulocytic dysplasia continued for 20 days in association with increased expression of CD69 and IL-4, but reduced IL-10; with resolution, this profile reversed to higher IL-10 expression and counter-balanced circannual cycling of IL-4 and IL-10 thereafter over 7 months. Along with immune cell subset and cytokine correlates monitored over 2 years, these observations offer unique insights into the expected changes in myelopoiesis and natural resolution in otherwise healthy young individuals in response to acute inflammation and cytokine storm in the absence of concomitant infection or comorbidity.
- |||||||||| theralizumab (TAB08) / TheraMab
Clinical, Journal, Cytokine storm: Patients with gastrointestinal irritability after TGN1412-induced cytokine storm displayed selective expansion of gut-homing αβ and γδT cells. (Pubmed Central) - Mar 31, 2021
This subset of patients with intestinal symptoms also displayed a striking and persistent expansion of putative Vδ2 γδT cells in the circulation which declined over a 2-year period following drug infusion, concordant with subsiding gut symptoms. These data demonstrate that TGN1412-induced gastrointestinal symptoms were associated with dysregulation of the 'gut-homing' pool of blood αβ and γδT cells, induced directly by the antibody and/or arising from the subsequent cytokine storm.
- |||||||||| theralizumab (TAB08) / TheraMab
Biomarker, Journal, Cytokine storm: Are all cytokine storms the same? (Pubmed Central) - Mar 26, 2021
Common approaches to treating CRS in other conditions are now applied to COVID-19 and, although some patients respond, it begs the following questions: (1) are all cytokine storms the same regardless of initiating insult, (2) can treatments be considered equally for all CRS events at any phase of the response, (3) can CRS be predicted based on dynamic acute biomarkers and, (4) should patients with CRS undergo long-term monitoring for secondary effects? The aim of this commentary is not to provide a review of COVID-19 pathophysiology or of cytokine storm, but rather to establish a foundation which could act as a platform to inform treatment approaches to CRS, regardless of cause, and the short- and long-term follow-up which may be necessary for affected patients.
- |||||||||| theralizumab (TAB08) / TheraMab
Journal: Functional differences and similarities in activated peripheral blood mononuclear cells by lipopolysaccharide or phytohemagglutinin stimulation between human and cynomolgus monkeys. (Pubmed Central) - Mar 13, 2021
However, the failures of preclinical studies to predict a life-threatening "cytokine storm", which, for instance, rapidly occurred in six healthy volunteers with the CD28 superagonist monoclonal antibody (mAb) TGN1412 in the first-in-human phase I clinical trial, have emphasized a need to clarify the differences between human and monkey immune systems...Moreover, there were some differences in antigen processing and presentation, and the interferon gamma (INF-γ)-mediated signaling pathway in these species detected by gene expression profile study. In conclusion, this is the first study to compare data on the responses of PBMCs to PHA and LPS in humans versus cynomolgus monkeys, and these findings may provide crucial insights into translating non-human primate (NHP) studies into human trials.
- |||||||||| theralizumab (TAB08) / TheraMab
Preclinical, Journal, Cytokine release syndrome: A rapid, sensitive, and reproducible in vivo PBMC humanized murine model for determining therapeutic-related cytokine release syndrome. (Pubmed Central) - Mar 12, 2021
Our data show that therapeutic-stimulated cytokine release in these PBMC-based NSG models captures the variation in cytokine release between individual donors, is drug dependent, occurs in the absence of acute xeno-GVHD, highlighting the specificity of the assay, and shows a robust response following treatment with a TGN1412 analog, a CD28 superagonist. Overall our results demonstrate that PBMC-engrafted NSG models are rapid, sensitive, and reproducible platforms to screen novel therapeutics for CRS.
- |||||||||| theralizumab (TAB08) / TheraMab
Journal: Human Fcγ receptors compete for TGN1412 binding which determines the antibody's effector function. (Pubmed Central) - May 25, 2020
In line with this, Fc?RI Fc?RII but not Fc?RI Fc?RII monocytes mediate TGN1412-induced T cell proliferation. Collectively, by using TGN1412 as example, our results indicate that binding of monomeric IgG subclasses does not predict the Fc?R-mediated effector function which has major implications for the design of therapeutic mAbs.
- |||||||||| Humira (adalimumab) / Eisai, AbbVie, theralizumab (TAB08) / TheraMab
Preclinical, Journal: Evaluation of a TGN1412 analogue using in vitro assays and two immune humanized mouse models. (Pubmed Central) - Apr 10, 2020
These results suggest that the TGN1412A produces similar results in vitro to the original TGN1412 monoclonal antibody. The BLT immune humanized mice but not the CD34 humanized mice produce both robust and specific cytokine responses and may represent a pre-clinical model to identify CRS.
- |||||||||| theralizumab (TAB08) / TheraMab
Preclinical, Review, Journal: Stem cell models as an in vitro model for predictive toxicology. (Pubmed Central) - Feb 14, 2020
However, animal models are imperfect proxies for human toxicity and there have been several high-profile cases of failure of animal models to predict human toxicity e.g. fialuridine, TGN1412 which highlight the need for improved predictive models of human toxicity...However, insufficient maturity, particularly in the case of hepatocyte-like cells, means that their widespread use is not currently a feasible method to tackle the complex issues of off-target and often unpredictable toxicity of novel compounds. This review discusses the current state of the art for modelling clinically relevant toxicities, e.g. cardio- and hepatotoxicity, alongside the emerging need for modelling gastrointestinal toxicity and seeks to address whether stem cell technologies are a potential solution to increase the accuracy of ADR predictivity in humans.
- |||||||||| BIA 10 2474 / Eisai, theralizumab (TAB08) / TheraMab
Clinical, Journal: 18 World Congress of Basic and Clinical Pharmacology: thought-provoking lectures on drug safety issues. (Pubmed Central) - Dec 29, 2019
Areas covered: Of the 380 invited lectures, this report reviews the opening presentation on immune checkpoint inhibitors and three talks dealing with drug safety issues (irreproducibility of nonclinical data, clinical Phase 1 catastrophes by TGN1214 and BIA-102474-101 in healthy volunteers, and Phase I sentinel dosing to reduce risk to clinical study participants). Expert opinion: The nonclinical safety assessment of drug candidates preceding clinical investigations requires the adoption of more human predictable biological assays and a careful and critical analysis of all available knowledge on a candidate to ensure the safety of clinical trial participants.
- |||||||||| theralizumab (TAB08) / TheraMab
Preclinical, Journal: Development of transplant immunosuppressive agents - considerations in the use of animal models. (Pubmed Central) - May 2, 2019
...The 2006 highly publicized case of the 'elephant man' TGN 1412 drug trial highlights the importance of being cogent of the limitations of animal models...Animal models are also costly and raise ethical concerns. However, there is currently no way to recreate the complex environment of the human immune system purely in vitro.
- |||||||||| theralizumab (TAB08) / TheraMab
Clinical, Journal: TGN-1412 and BIA-2474 Trials with Tragic End: Lessons Learnt To Make Clinical Trials Safer. (Pubmed Central) - Apr 11, 2019
However, there is currently no way to recreate the complex environment of the human immune system purely in vitro. Inclusion of above mentioned measures in clinical trials are bound to make them safer and may help in pacifying the insecurity that has emerged among humans to participate in clinical trials.
- |||||||||| theralizumab (TAB08) / TheraMab
Trial completion date, Trial termination, Trial primary completion date: TAB08 in Patients With Systemic Lupus Erythematosus (SLE), Not Adequately Controlled With Current Treatment (clinicaltrials.gov) - May 30, 2018
P2, N=60, Terminated,
Inclusion of above mentioned measures in clinical trials are bound to make them safer and may help in pacifying the insecurity that has emerged among humans to participate in clinical trials. Trial completion date: Jun 2017 --> May 2018 | Recruiting --> Terminated | Trial primary completion date: Mar 2017 --> May 2018; Administrative reasons
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