urelumab (BMS-663513)

Overall, the c-MET x CD137 BsAb exhibits a promising developability profile as a tumor-targeted immune agonist by minimizing off-target effects while effectively delivering immune agonism. It has the potential to overcome resistance to anti-PD-(L)1 therapies.

Although the addition of urelumab at these doses was tolerable, preliminary response rates did not indicate an evident additive benefit. Nevertheless, the positive pharmacodynamics effects observed with urelumab and the high response rate in treatment-naive patients with melanoma warrant further investigation of other anti-CD137 agonist agents for treatment of cancer.

TIL manufactured with assistance of 4-1BB and CD3 agonism is feasible and treatment is associated with no new safety signals. While no responses were observed, a significant portion of patients achieved SD suggesting early/partial immunological effect. Further research is required to identify factors associated with resistance and functionally enhance T cells for a more effective therapy.

P2, N=15, Active, not recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Development of the first-generation CD137-agonist monotherapies utomilumab and urelumab was unsuccessful due to low antitumor efficacy mediated by the epitope recognized on CD137 or hepatotoxicity mediated by FcγR ligand-dependent CD137 activation, respectively. Compared with 3H3, a murine surrogate of urelumab, FS122m and chimeric M9657 displayed significantly lower on-target/off-tumor toxicity. Taken together, M9657 exhibits a promising profile for development as a tumor-targeting immune agonist with potent anticancer activity without systemic immune activation and associated hepatotoxicity.

P2, N=15, Active, not recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial primary completion date: Jul 2023 --> Jul 2024

P1, N=63, Completed, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Active, not recruiting --> Completed

LM-SBRT did not significantly increase the risk for hepatotoxicity in patients receiving ICI when respecting the above dose constraints. Risk for hepatotoxicity appears to be driven by dual agent ICI and underlying liver disease.

Moreover, monoclonal antibodies that target-4-1BB, for example, Urelumab and Utomilumab, are widely used in the treatments of B cell non-Hodgkin lymphoma, lung cancer, breast cancer, soft tissue sarcoma, and other solid tumors. As such, a deeper understanding of 4-1BB will contribute to improvements in cancer immunotherapy. This review provides a comprehensive analysis of current 4-1BB studies, with a focus on the use of targeting-4-1BB antibodies and 4-1BB activation domains in CAR-T cells for the treatment of cancer.

We enrolled patients with resectable pancreatic adenocarcinoma into such a platform trial (NCT02451982) to receive pancreatic cancer GVAX vaccine with low-dose cyclophosphamide alone (Arm A; n = 16), with anti-PD-1 antibody nivolumab (Arm B; n = 14), and with both nivolumab and anti-CD137 agonist antibody urelumab (Arm C; n = 10), respectively...GVAX+nivolumab+urelumab demonstrates numerically-improved disease-free survival (HR = 0.55, p = 0.242; HR = 0.51, p = 0.173) and overall survival (HR = 0.59, p = 0.377; HR = 0.53, p = 0.279) compared to GVAX and GVAX+nivolumab, respectively, although not statistically significant due to small sample size. Therefore, neoadjuvant and adjuvant GVAX with PD-1 blockade and CD137 agonist antibody therapy is safe, increases intratumoral activated, cytotoxic T cells, and demonstrates a potentially promising efficacy signal in resectable pancreatic adenocarcinoma that warrants further study.

P2, N=76, Recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: Jun 2024 --> Dec 2025 | Trial primary completion date: Jun 2023 --> Dec 2024

It induced superior 4-1BB activity (EC50: 1.07 nM) than benchmark antibody Urelumab (EC50: 3.38 nM) in the presence of cells expressing CEACAM5. LM-24C5 was well tolerated in hu4-1BB/4-1BBL double-transgenic mice at a dose of 100mg/kg given once weekly for 2 weeks. In summary, LM-24C5 is a novel CEACAM5 dependent 4-1BB bispecific agonist antibody that could redirect and activate T cells to CEACAM5 positive tumor cells by engaging 4-1BB antigen, thus positioned as a potential novel therapy for colorectal carcinoma and other CEACAM5 positive tumors.

We compared specimens from 3 treatment arms for downstream analysis: Arm A: an allogeneic whole cell vaccine, GVAX (n=7); Arm B: GVAX and nivolumab (n=4); Arm C: GVAX, nivolumab, and urelumab (n=4)... Analysis of combination GVAX, PD-1 inhibition and CD137 agonist therapy demonstrated changes in multiple immune cell proportions and their functional pathways. These data provide new evidence that PDACs can become T cell rich and respond to combination immunotherapies.

The addition of stimulatory agents such as anti-4-1BB (Urelumab) during the PreREP phase increased cell yields, as well as skewing the population towards a non-exhausted CD8+ phenotype (reduced expression of PD1, LAG3, TIM3)...And most importantly these TILs are reactive and specific for tumor antigens. Following additional assessment of in vitro cytotoxicity against matched tumor neurospheres in vitro we will evaluate safety and feasibility of our novel TIL approach in patients with glioblastoma.

The first molecule of this class, BT7480, a Nectin-4-dependent CD137 (4-1BB) agonist, entered clinical trials in 2021 in patients with solid tumors associated with Nectin-4 expression...The kinetics and extent of the immune microenvironment modulation differentiated BT7455 from both a checkpoint inhibitor (anti-mouse PD-1) as well as an anti-CD137 agonist antibody (urelumab analogue)...Cancer Res 2020; 80:5300 4Xiao, et al. J Hematol Oncol 2020; 13:114.

In the clinic, the agonist antibody urelumab showed evidence for single-agent activity against melanoma and non-Hodgkin lymphoma but caused severe liver inflammation in a fraction of the patients...CD137 (4-1BB) is a costimulatory receptor of T and natural killer lymphocytes whose activity can be exploited in cancer immunotherapy strategies as discovered 25 years ago. Following initial attempts that met unacceptable toxicity, new waves of constructs acting agonistically on CD137 are being developed in patients, offering signs of clinical and pharmacodynamic activity with tolerable safety profiles.

P1, N=60, Completed, University of Chicago | Active, not recruiting --> Completed

P1, N=63, Active, not recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: Apr 2023 --> Oct 2023 | Trial primary completion date: Dec 2022 --> Oct 2023

P2, N=15, Active, not recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | N=44 --> 15 | Trial completion date: Dec 2022 --> Dec 2024 | Trial primary completion date: Dec 2021 --> Jul 2023

P1, N=11, Completed, H. Lee Moffitt Cancer Center and Research Institute | Active, not recruiting --> Completed

Compared with anti-4-1BB parent antibody and urelumab, HK013 induced weaker FcγR-mediated 4-1BB activation. Conclusions IgG1-based HK013-1 prevents tumor development by directly killing tumor cells and depleting Treg to relieve immunosuppression. Preclinical studies have shown that IgG1-based HK013-1 has good antitumor activity and safety, which may further develop its clinical potential.

1 The first molecule of this class, BT7480, a Nectin-4-dependent CD137 (4-1BB) agonist, entered clinical trials in 2021 in patients with solid tumors associated with Nectin-4 expression...The kinetics and extent of the immune microenvironment modulation differentiated BT7455 from both a checkpoint inhibitor (anti-mouse PD-1) as well as an anti-CD137 agonist antibody (Urelumab analogue)...Conclusions BT7455 is a highly potent EphA2 expression-dependent CD137 agonist with optimal target binding, pharmacologic, and pharmacokinetic properties that enable intermittent dosing for curative effect through modulation of the tumor immune microenvironment in syngeneic mouse models. BT7455 is currently being evaluated in IND-enabling safety studies.

This study demonstrated that HuB6 should be a suitable candidate for further clinical development and a potential agent for CRC immunotherapy.

P1, N=63, Active, not recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial primary completion date: Sep 2022 --> Dec 2022

P2, N=44, Active, not recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Recruiting --> Active, not recruiting

P1, N=63, Active, not recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: Apr 2022 --> Apr 2023 | Trial primary completion date: Mar 2021 --> Sep 2022

We report the feasibility of robustly expanding a T-cell repertoire recapitulating the clonal hierarchy of the T cells in the NSCLC tumor, including a large number of putative tumor-specific TIL clones, using the TIL 3.0 methodology. If scaled up and employed as a sole expansion platform, the robustness and speed of TIL 3.0 may facilitate the testing of TIL-ACT approaches in NSCLC.

P1, N=60, Active, not recruiting, University of Chicago | Trial completion date: Feb 2022 --> Jul 2022

Targeting CLDN18.2 with the monoclonal antibody (mAb) Zolbetuximab has achieved moderate clinical benefit with controllable toxicity...However, inherent on-target related toxic effects in the liver was observed during the clinical development of the monoclonal agonist antibody Urelumab... In summary, a bispecific antibody targeting CLDN18.2 and 4-1BB was developed, which displayed potent anti-tumor efficacy with strong immunological memory and has shown good safety in NHPs. Moreover, the molecule has high selectivity to CLDN18.2. The molecule shall enter clinical trials by early 2022.

Functional evaluation of CLDN6X4-1BB BsAb indicated that the activation of 4-1BB signaling was dependent on CLDN6 expression on tumor cells and the activity was stronger than reference 4-1BB monoclonal antibody urelumab...From the safety perspective, there were no significant changes in liver enzymes or liver histopathology following repeated BsAb administration, suggesting little risks for liver toxicity commonly induced by other 4-1BB agonist antibodies.Conclusions We have successfully generated a novel CLDN6-targeted 4-1BB bispecific antibody which could induce potent 4-1BB stimulation and anti-tumor activity in a CLDN6-dependent manner while minimizing the risk of liver toxicity. Taken together, these data support further development of CLDN6 X 4-1BB bispecific antibody towards IND and clinical trial in 2022.

Our data confirm the immunosuppressive function of B7H3 and demonstrate the immunoregulatory function of TJ271 as evidenced by the activation of cytolytic T cell and NK cells, reinvigoration of exhausted cells, and suppression of M2-like myeloid cells. These findings provide rationale for combination therapy with blockade of B7-H3 by TJ271 with other immunotherapies to achieve increased clinical efficacy against cancers.

4-1BB agonizing monoclonal antibodies have thus far failed to progress beyond early clinical development, either due to hepatic toxicities caused by FcγR-crosslinking (urelumab) or due to low clinical activity (utomilumab). When tumor-bearing mice were treated IP with Opal at 1 mg/kg, 7/10 mice exhibited durable cures without significant body weight loss. Taken together, the preclinical data suggests that Opal may exhibit single-agent activity in solid tumors by conditionally activating effector cells in the tumor microenvironment via 4-1BB agonism while concurrently blocking the PD1/PDL1/PDL2 axis.

P2, N=44, Recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: May 2022 --> Dec 2022

P2, N=76, Recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Phase classification: P1/2 --> P2

P1/2, N=76, Recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: Feb 2023 --> Jun 2024 | Trial primary completion date: Jun 2022 --> Jun 2023

P2, N=44, Recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial primary completion date: Sep 2021 --> Dec 2021

Methods TIL from resected NSCLC tumors were cultured using 1) the traditional method using IL-2 alone in 24-well plates (TIL 1.0) or 2) IL-2 in combination with agonistic antibodies against CD3 and 4-1BB (Urelumab) in a G-Rex flask (TIL 3.0)...Conclusions This study reports the feasibility of using the TIL 3.0 methodology to robustly expand a CD8+ T-cell repertoire which maintains the respective clonal hierarchy in NSCLC tumors and enriches for putative tumor-specific TIL clones. The robustness and speed of the new process may facilitate testing and implementing effective TIL ACT in NSCLC.

Early efforts to develop 4-1BB targeted agonists were limited by poor tolerability (Urelumab) or insufficient efficacy (Utomilumab). INBRX-105 is currently being evaluated in patients with advanced solid tumors in a first-in-human trial (NCT03809624). Trial Registration INBRX-105 is currently being evaluated in patients with advanced solid tumors in a first-in-human trial (NCT03809624).

Here, we have demonstrated that the anti-CD137 agonist urelumab can overcome TGFβ-mediated inhibition of human NK-cell proliferation and antitumor function. Bioinformatic analysis pointed to IFNG as the driver of the association between NK cells and clinical response to trastuzumab in HER2-positive primary breast cancer patients, highlighting the translational relevance of the CD137 costimulatory axis for enhancing IFNγ production. Our data reveals CD137 as a targetable checkpoint for overturning TGFβ constraints on NK-cell antitumor responses.

P1, N=11, Active, not recruiting, H. Lee Moffitt Cancer Center and Research Institute | Trial completion date: Dec 2021 --> Dec 2023 | Trial primary completion date: Aug 2021 --> Oct 2023