TNB-486 induces potent tumor cell cytotoxicity coupled with low cytokine release in preclinical models of B-NHL

Malik-Chaudhry, Harbani K.; Prabhakar, Kirthana; Ugamraj, Harshad; Boudreau, Andrew; Buelow, Benjamin; Dang, Kevin; Davison, Laura; Harris, Katherine E.; Jorgensen, Brett; Ogana, Heather; Pham, Duy; Schellenberger, Ute; Schooten, Wim van; Buelow, Roland; Iyer, Suhasini; Trinklein, Nathan D.; Rangaswamy, Udaya S.

doi:10.1080/19420862.2021.1890411

Cited by 19 publications

(16 citation statements)

References 50 publications

(74 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Using genetically engineered transgenic rats (UniRat and OmniFlic) that express fully human IgG antibodies together with an NGS-based antibody discovery pipeline (TeneoSeek), [25][26][27][28] we have developed TNB-585. Methods for generating antibodies targeting CD3 in OmniFlic animals have been previously described.…”

Section: Materials and Methods Immunization Ngs Clonotype Analysis And Cloningmentioning

confidence: 99%

Attenuating CD3 affinity in a PSMAxCD3 bispecific antibody enables killing of prostate tumor cells with reduced cytokine release

Dang

Castello

Clarke

et al. 2021

J Immunother Cancer

Self Cite

View full text Add to dashboard Cite

BackgroundTherapeutic options currently available for metastatic castration-resistant prostate cancer (mCRPC) do not extend median overall survival >6 months. Therefore, the development of novel and effective therapies for mCRPC represents an urgent medical need. T cell engagers (TCEs) have emerged as a promising approach for the treatment of mCRPC due to their targeted mechanism of action. However, challenges remain in the clinic due to the limited efficacy of TCEs observed thus far in solid tumors as well as the toxicities associated with cytokine release syndrome (CRS) due to the usage of high-affinity anti-CD3 moieties such as OKT3.MethodsUsing genetically engineered transgenic rats (UniRat and OmniFlic) that express fully human IgG antibodies together with an NGS-based antibody discovery pipeline, we developed TNB-585, an anti-CD3xPSMA TCE for the treatment of mCRPC. TNB-585 pairs a tumor-targeting anti-PSMA arm together with a unique, low-affinity anti-CD3 arm in bispecific format. We tested TNB-585 in T cell-redirected cytotoxicity assays against PSMA+ tumor cells in both two-dimensional (2D) cultures and three-dimensional (3D) spheroids as well as against patient-derived prostate tumor cells. Cytokines were measured in culture supernatants to assess the ability of TNB-585 to induce tumor killing with low cytokine release. TNB-585-mediated T cell activation, proliferation, and cytotoxic granule formation were measured to investigate the mechanism of action. Additionally, TNB-585 efficacy was evaluated in vivo against C4-2 tumor-bearing NCG mice.ResultsIn vitro, TNB-585 induced activation and proliferation of human T cells resulting in the killing of PSMA+ prostate tumor cells in both 2D cultures and 3D spheroids with minimal cytokine release and reduced regulatory T cell activation compared with a positive control antibody that contains the same anti-PSMA arm but a higher affinity anti-CD3 arm (comparable with OKT3). In addition, TNB-585 demonstrated potent efficacy against patient-derived prostate tumors ex vivo and induced immune cell infiltration and dose-dependent tumor regression in vivo.ConclusionsOur data suggest that TNB-585, with its low-affinity anti-CD3, may be efficacious while inducing a lower incidence and severity of CRS in patients with prostate cancer compared with TCEs that incorporate high-affinity anti-CD3 domains.

show abstract

Section: Materials and Methods Immunization Ngs Clonotype Analysis And Cloningmentioning

confidence: 99%

Attenuating CD3 affinity in a PSMAxCD3 bispecific antibody enables killing of prostate tumor cells with reduced cytokine release

Dang

Castello

Clarke

et al. 2021

J Immunother Cancer

Self Cite

View full text Add to dashboard Cite

show abstract

“…To examine the specific binding of the selected scFv-Fc and IgG1 antibodies to the EphA2 receptor on the surface of tumor cells, flow cytometry was performed as previously described [ 56 , 57 ]. The purified bivalent recombinant antibody, scFv-Fc; and full-length antibody, IgG1, were added to PC-3 and A549 cells (2 × 10 5 in 1 × PBS) as primary antibodies with final concentrations set at 1.25 μg/mL, 5 μg/mL, and 20 μg/mL for an incubation at 4°C for 1 h. The final concentration in the blank group was 1.25 μg/mL.…”

Section: Methodsmentioning

confidence: 99%

Fully human recombinant antibodies against EphA2 from a multi-tumor patient immune library suitable for tumor-targeted therapy

Yang

Nian

et al. 2021

Bioengineered

View full text Add to dashboard Cite

Enhanced EphA2 expression is observed in a variety of epithelial-derived malignancies and is an important target for anti-tumor therapy. Currently, Therapeutic monoclonal antibodies against immune checkpoints have shown good efficacy for tumor treatment. In this study, we constructed an immune single-chain fragment variable (scFv) library using peripheral blood mononuclear cells (PBMCs) from 200 patients with a variety of malignant tumors. High affinity scFvs against EphA2 can be easily screened from the immune library using phage display technology. Anti-EphA2 scFvs can be modified into any form of recombinant antibody, including scFv-Fc and full-length IgG1 antibodies, and the recombinant antibody affinity was improved following modification. Among the modified anti-EphA2 antibodies the affinity of 77-IgG1 was significantly increased, reaching a pmol affinity level (10 −12 ). We further demonstrated the binding activity of recombinant antibodies to the EphA2 protein, tumor cells, and tumor tissues using macromolecular interaction techniques, flow cytometry and immunohistochemistry. Most importantly, both the constructed scFvs-Fc, as well as the IgG1 antibodies against EphA2 were able to inhibit the growth of tumor cells to some extent. These results suggest that the immune libraries from patients with malignant tumors are more likely to screen for antibodies with high affinity and therapeutic effect. The constructed fully human scFv immune library has broad application prospects for specific antibody screening. The screened scFv-Fc and IgG1 antibodies against EphA2 can be used for the further study of tumor immunotherapy.

show abstract

“…The molecule is constituted of a high-affinity anti-CD19 heavy chain and a low-affinity anti-CD3 light chain, the latter with low-activating potential. In vitro models have demonstrated that the cytokine secretion (i.e., IL-2, IFN-γ, IL-6, IL-10, and TNF) by CD3 + cells is minimal even at saturating doses for tumor lysis ( 34 , 35 ). A phase 1 study (NCT04594642) is currently testing TNB-486 for R/R B-cell non-Hodgkin lymphoma in patients who have received 2 or more prior lines of therapy.…”

Section: Bispecific T Cell Engagersmentioning

confidence: 99%

CD19-Targeted Immunotherapies for Diffuse Large B-Cell Lymphoma

et al. 2022

View full text Add to dashboard Cite

Surgical resection, chemotherapy and radiotherapy were, for many years, the only available cancer treatments. Recently, the use of immune checkpoint inhibitors and adoptive cell therapies has emerged as promising alternative. These cancer immunotherapies are aimed to support or harness the patient’s immune system to recognize and destroy cancer cells. Preclinical and clinical studies, based on the use of T cells and more recently NK cells genetically modified with chimeric antigen receptors retargeting the adoptive cell therapy towards tumor cells, have already shown remarkable results. In this review, we outline the latest highlights and progress in immunotherapies for the treatment of Diffuse Large B-cell Lymphoma (DLBCL) patients, focusing on CD19-targeted immunotherapies. We also discuss current clinical trials and opportunities of using immunotherapies to treat DLBCL patients.

show abstract

TNB-486 induces potent tumor cell cytotoxicity coupled with low cytokine release in preclinical models of B-NHL

Cited by 19 publications

References 50 publications

Attenuating CD3 affinity in a PSMAxCD3 bispecific antibody enables killing of prostate tumor cells with reduced cytokine release

Attenuating CD3 affinity in a PSMAxCD3 bispecific antibody enables killing of prostate tumor cells with reduced cytokine release

Fully human recombinant antibodies against EphA2 from a multi-tumor patient immune library suitable for tumor-targeted therapy

CD19-Targeted Immunotherapies for Diffuse Large B-Cell Lymphoma

Contact Info

Product

Resources

About