An optimal antitumor response by a novel CEA/CD3 bispecific antibody for colorectal cancers

Wang, Ninghai; Patel, Hiral R.; Schneider, Irene C.; Kai, Xin; Varshney, Ankur Nandan; Zhou, Li

doi:10.1093/abt/tbab009

Cited by 10 publications

(6 citation statements)

References 28 publications

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“…2A2-long-tandem induced a significantly lower release of IFNg with a EC50 of 8.4 nM and an IFNg release Emax of 4,400 pg/mL whereas the EC50 and Emax for 2A2-short-tandem was 4.5 nM and 8,400 pg/mL, respectively. In this case, consistent with multiple reports (24,25,46), decoupling of cytotoxicity from cytokine release was mainly restricted to the maximum release of IFNg. 2A2-long-tandem showed a higher decoupling ratio of 0.065 in comparison to 2A2-short tandem (0.034) (Figure 1B).…”

Section: Design Of Different Ror1 X Cd3 Formatssupporting

confidence: 92%

Using protein geometry to optimize cytotoxicity and the cytokine window of a ROR1 specific T cell engager

Zhou,

Geyer,

Happel

et al. 2024

Front. Immunol.

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T cell engaging bispecific antibodies have shown clinical proof of concept for hematologic malignancies. Still, cytokine release syndrome, neurotoxicity, and on-target-off-tumor toxicity, especially in the solid tumor setting, represent major obstacles. Second generation TCEs have been described that decouple cytotoxicity from cytokine release by reducing the apparent binding affinity for CD3 and/or the TAA but the results of such engineering have generally led only to reduced maximum induction of cytokine release and often at the expense of maximum cytotoxicity. Using ROR1 as our model TAA and highly modular camelid nanobodies, we describe the engineering of a next generation decoupled TCE that incorporates a “cytokine window” defined as a dose range in which maximal killing is reached but cytokine release may be modulated from very low for safety to nearly that induced by first generation TCEs. This latter attribute supports pro-inflammatory anti-tumor activity including bystander killing and can potentially be used by clinicians to safely titrate patient dose to that which mediates maximum efficacy that is postulated as greater than that possible using standard second generation approaches. We used a combined method of optimizing TCE mediated synaptic distance and apparent affinity tuning of the TAA binding arms to generate a relatively long but persistent synapse that supports a wide cytokine window, potent killing and a reduced propensity towards immune exhaustion. Importantly, this next generation TCE induced significant tumor growth inhibition in vivo but unlike a first-generation non-decoupled benchmark TCE that induced lethal CRS, no signs of adverse events were observed.

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Section: Design Of Different Ror1 X Cd3 Formatssupporting

confidence: 92%

Using protein geometry to optimize cytotoxicity and the cytokine window of a ROR1 specific T cell engager

Zhou,

Geyer,

Happel

et al. 2024

Front. Immunol.

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“… 61–64 In vitro , lower CD3 binder affinity is associated with reduced tumor cell killing and reduced cytokine release. 61 , 62 In vivo , a low-affinity CD3 binder retains efficacy while reducing cytokine release and ensuring optimal bio-distribution and accumulation in the tumor. 65 Additionally, Dang et al .…”

Section: Engineering Of T Cell Engager Formatmentioning

confidence: 99%

Novel strategies for the mitigation of cytokine release syndrome induced by T cell engaging therapies with a focus on the use of kinase inhibitors

et al. 2022

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T cell engaging therapies, like CAR-T cells and T cell engagers, redirect T cells toward tumor cells, facilitating the formation of a cytotoxic synapse and resulting in subsequent tumor cell killing. T cell receptor or CAR-T downstream signaling triggers a release of pro-inflammatory cytokines, which can induce a Cytokine Release Syndrome (CRS). The incidence of CRS is still hardly predictable among individuals and remains one of the major dose-limiting safety liabilities associated with on-target activity of T cell engaging therapies. This emphasizes the need to elaborate mitigation strategies, which reduce cytokine release while retaining efficacy. Here, we review pre-clinical and clinical approaches applied for the management of CRS symptoms in the context of T cell engaging therapies, highlighting the use of tyrosine kinase inhibitors as an emerging mitigation strategy. In particular, we focus on the effects of Bruton’s tyrosine kinase (BTK), Src family including Lck, mammalian target of rapamycin (mTOR) and Janus tyrosine kinase (JAK) inhibitors on T cell functionality and cytokine release, to provide a rationale for their use as mitigation strategies against CRS in the context of T cell engaging therapies.

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“…Indeed, it has been reported that a BsAb, named RO6958688, targeting CEA and CD3, increase T cell infiltration into a xenograft colon carcinoma in mice co-grafted with PBMCs, converting a PD-L1 negative tumor in a PD-L1 positive one [ 3 , 7 , 8 ]. Early results showed enhanced activity of CEA/CD3 targeting BsAb, when combined with the anti-PD-L1 antibody Atezolizumab in patients with metastatic colorectal cancer [ 33 – 35 ]. Therefore, the immunosuppressive signals in TME represent a critical obstacle for effective immunotherapies, suggesting that inhibition of immune checkpoints could potentiate the efficacy of T cell engaging therapy [ 10 , 11 , 36 ].…”

Section: Discussionmentioning

confidence: 99%

Novel tri-specific tribodies induce strong T cell activation and anti-tumor effects in vitro and in vivo

Passariello

Yoshioka²,

Takahashi³

et al. 2022

J Exp Clin Cancer Res

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Background Immunotherapy based on Bi-specific T Cell Engagers (TCE) represents one of the most attractive strategy to treat cancers resistant to conventional therapies. TCE are antibody-like proteins that simultaneously bind with one arm to a Tumor Associated Antigen (TAA) on cancer cells and with the other one to CD3 complex on a T-cell to form a TCR-independent immune synapse and circumvent Human Leucocyte Antigen restriction. Among them, the tribodies, such as Tb535H, a bi-specific molecule, made up of a Fab and a scFv domain both targeting 5T4 and another scFv targeting CD3, have demonstrated anti-tumor efficacy in preclinical studies. Methods Here, we generated five novel tri-specific and multi-functional tribodies, called 53X tribodies, composed of a 5T4 binding Fab arm and a CD3 binding scFv, but differently from the parental Tb535H, they contain an additional scFv derived from an antibody specific for an immune checkpoint, such as PD-1, PD-L1 or LAG-3. Results Compared with the parental Tb535H bi-specific T cell engager targeting 5T4, the novel 53X tribodies retained similar binding properties of Tb535H tribody, but showed enhanced anti-tumor potency due to the incorporation of the checkpoint inhibitory moiety. In particular, one of them, called 53L10, a tri-specific T cell engager targeting 5T4, CD3 and PD-L1, showed the most promising anti-tumor efficacy in vitro and led to complete tumor regression in vivo. Conclusions The novel tribodies have the potential to become strong and safe therapeutic drugs, allowing to reduce also the cost of production as one single molecule contains three different specificities including the anti-TAA, anti-CD3 and anti-IC binding arms.

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An optimal antitumor response by a novel CEA/CD3 bispecific antibody for colorectal cancers

Cited by 10 publications

References 28 publications

Using protein geometry to optimize cytotoxicity and the cytokine window of a ROR1 specific T cell engager

Using protein geometry to optimize cytotoxicity and the cytokine window of a ROR1 specific T cell engager

Novel strategies for the mitigation of cytokine release syndrome induced by T cell engaging therapies with a focus on the use of kinase inhibitors

Novel tri-specific tribodies induce strong T cell activation and anti-tumor effects in vitro and in vivo

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