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Star target of tumor immunity: CD137 Double Antibodies and Combo Strategy
Star target of tumor immunity: CD137 Double Antibodies and Combo Strategy. The tumor necrosis factor receptor superfamily (TNFRSF) is a 29-member protein superfamily that plays an important role in the human immune system.
CD137 (4-1BB) is one of the members of TNFRSF, and TNFRSF members are characterized by their ability to bind TNF through the formation of disulfide bonds rich in cysteine extracellular domains. Like other TNFRSF members, the three monomeric 4-2BB binds to trimerized CD137L to activate intracellular signaling.
CD137 is rapidly expressed on CD4+ and CD8+ T cells after antigen exposure. CD137 and the T cell receptor (TCR) on activated T cells can transmit costimulatory signals to T cells, which leads to T cell proliferation, survival, memory formation and Stronger cytotoxicity and effector function of cytokine production.
IL-2 or IL-15 can induce NK cells to express CD137, stimulate NK cells to produce IFN-γ, and further support T cell activation. CD137 signal can promote the proliferation and survival of CD8+ T cells, enhance cytotoxicity and metabolic adaptability, and can generate CD8+ memory T (Tm) cells. After CD137 is activated, both CD4+ and CD8+ T cells produce IL-2 and IFN-γ. The function of CD137 in T regulatory cells (Treg) is controversial. CD137 activation can lead to the proliferation of Treg, but it can change the cytotoxicity or auxiliary effect of Treg.
Monocytes also express CD137. Activating CD137 can induce the production of TNF-α and IL-8, inhibiting IL-10; CD137 activation also helps monocytes differentiate into dendritic cells (DC), and also helps DC cell production IL-12 and IL-6. However, CD137 activation also polarized monocytes into M2 macrophages and promoted B cell apoptosis.
01. CD137 double antibody
In clinical trials targeting the TNFRSF costimulatory receptor, CD137 seems to be the most promising target.
In order to reduce the toxicity of the systemic CD137 agonist to the liver while maintaining the efficacy, a bispecific molecule that also binds to the tumor-associated antigen (TAA) is used to target CD137, and the CD137+T cell agonist is restricted to the tumor microenvironment It seems to be an ideal method.
First, only antigen-exposed T cells (CD137+T cells) are involved in targeting TAA. Therefore, cytokine release syndrome (CRS) targeting non-tumor toxicity can be minimized.
Second, CD137 targeting bispecific antibodies may be more tolerant to antigen loss than CD3 targeting bispecific antibodies, because CD137 stimulation can expand tumor-reactive memory T cells independently of MHC or antigen. When the memory T cell pool expands, it can recognize a variety of tumor antigens.
Finally, compared to CD3+ T cell targeting, CD137 activation can reduce T cell failure. Data show that CD137 costimulation can restore the function of depleted CD8+TIL in mice, extend the duration of cytotoxic T lymphocytes (CTL), and enhance CTL function.
The above table summarizes the clinical research progress of CD137 targeting bispecific molecules.
A bispecific molecule targeting HER2 and CD137 is currently undergoing phase I clinical studies in HER2-positive solid tumors. Among patients who received effective dose treatment (n=33), 12% of patients achieved ORR, including 1 CR, disease control rate (DCR) was 52%, and there was no DLT report.
Strikingly, there are no reports of CRS or toxicity in the central nervous system, which highlights the further advantages of CD137 targeting and CD3 targeting bispecific compounds. PRS-343 has also been reported clinically in combination with atezolizumab, but the combined application seems to lack additive effects.
It is a bispecific antibody targeting PD-L1 and CD137. PD-L1 acts as a TAA, and GEN1046 also inhibits the signal of the PD-L1 pathway. In the phase 1 clinical trial, although the MTD was not reached, grade 3 liver toxicity was reported. Among the 56 patients who received effective dose treatment, there were 4 PRs, and the DCR was 65.6%. In the cohort expansion trial, the initial anti-tumor efficacy of NSCLC patients previously treated with checkpoint inhibitors was observed. These two studies support the application of CD137 targeting bispecific molecules in solid tumors.
RO7122290 and RO7227166
They are fusion proteins of unique CD137L trimer and anti-fibroblast activation protein (FAP) and CD19 Fab.
The safety and clinical efficacy of RO7122290 alone or in combination with atezolizumab were evaluated in a phase I clinical study. The clinical efficacy of monotherapy is limited, and the combination therapy with atezolizumab is not ideal. It is currently uncertain whether anti-drug antibodies (ADA) will have a negative impact on efficacy, because it has been reported that the positive rate of ADA reaches 20% in evaluable patients who have lost efficacy. RO7227166 is also undergoing the first phase of research.
It is another bispecific compound of PD-L1 and CD137, which is currently in the cohort expansion part of the Phase I clinical study. According to reports, the clinical efficacy of ES101/INBRX-105 monotherapy is stable in 8 of 18 patients, and a maximum reduction of 20% in tumor volume has been observed. The joint study with pembrolizumab is ongoing.
At present, in the first phase of clinical research, there are still many bispecific antibody molecules against CD137. Among them, CB307, targeting prostate-specific membrane antigen (PSMA), FS120 and GEN1042 are also very interesting, they simultaneously target two co-stimulatory receptors: OX40/CD137 and CD40/CD137.
02. Combination therapy of CD137 targeting molecules
The clinical studies of HPN424 and RO7122290 have shown the potential of combined application with PD-L1 inhibitors.
Utomilumab and pembrolizumab combined treatment were evaluated in 33 patients with solid tumors. The combined treatment achieved an ORR of 26%, including 1 CR. However, the comparison with pembrolizumab monotherapy is still unclear.
In melanoma and other malignant tumors, the efficacy of Urelumab combined with nivolumab has also been evaluated. Regardless of the status of PD-L1, the combination therapy has achieved the best response rate of 50% in melanoma, while the effect is not significant in other malignant tumors.
CD3 targeting bispecific antibody
Another interesting possibility in combination with CD137 is the CD3 targeting bispecific antibody.
In addition to the signal provided by CD3 stimulation, CD137-targeted bispecific antibody co-stimulation can provide a durable anti-tumor response. Importantly, the CD3 and CD137 bispecific molecules do not have to target the same TAA. In a preclinical mouse model, the combination of bispecific molecules targeting CD3/CEA and CD137L/FAP showed a synergistic anti-tumor effect. Compared with the single effect of the CD3/CEA bispecific antibody, the combined application was accompanied by tumors. Significant increase in CD8+ T cells.
Recently, the phase Ib study of RO7122290 in combination with cibisatamab (CEA x CD3 bispecific molecule) and obinutuzumab for colorectal cancer has been launched (NCT04826003).
ADCC enhancing antibody
Targeting CD137 may also enhance the efficacy of ADCC activity-dependent monoclonal antibody therapy due to the activation mechanism of NK cells. The effect of combination therapy of Urelumab and rituximab has been evaluated in patients with B-cell lymphoma. Although many of these drugs have higher exposure levels than MTD, responses have been observed.
In addition, the ORR of patients with non-Hodgkin’s lymphoma treated with utomilumab combined with rituximab was 21.2%. In order to confirm this preclinical hypothesis, whether CD137 agonists can enhance ADCC activity in humans, PRS-343 combined with ramucirumab and paclitaxel in the treatment of HER2-positive gastric cancer clinical research is starting.
03. The challenge of CD137 targeted therapy for solid tumors
First, it is necessary to establish a transformable preclinical model that can predict clinical safety and response. In addition to the immune response of the cancer type, it is also important to understand the organ-specific immune response. In addition, there are aspects of optimizing immune cell activation, including optimizing the molecular size of the drug to penetrate the tumor and activate T cells in the tumor environment, which is crucial.
However, if the size of the molecule is small enough, its duration in the circulatory system may not be long enough to reach the tumor effectively. In order to achieve better drug delivery by reducing the renal clearance of smaller bispecific molecules, a form that binds to albumin can be used. Both CB307 and NM21-1480 use HSA-coupled structures and are currently being studied in phase I clinical trials. In addition, since continuous exposure of T cells to antigens may lead to T cell failure, it is unclear which treatment half-life is most appropriate. In order to answer this question, clinical research on multiple dosing regimens may be required.
The optimization of patient selection for CD137-targeted molecules in clinical trials also needs to be explored. The expression of CD137+TIL in a variety of solid tumors has been detected at the mRNA level. However, so far, there has been no prospective clinical trial of CD137-targeted drugs based on CD137+TIL information. This is because the dynamic nature of CD137 expression makes it difficult to obtain definitive results. In fact, there is no data showing that the response to CD137 monoclonal antibody is related to the expression level of CD137 in the tumor microenvironment.
For PRS-343, clinical response can be seen at the dose level at which CD8+ T cell expansion is observed. However, CD8+ T cell expansion may prove to be a necessary condition for clinical efficacy, but it is not a sufficient condition, because even if observed By the time CD8+ T cells expanded, no clinical response was seen in other patients. Understanding the compensation pathway to maximize the cytotoxic activity of T cells while maintaining an appropriate margin of safety will require further research to pave the way for successful combination therapy.
Finally, CD137 activates an effective method to generate memory T cells, which may be the key to a long-lasting anti-cancer immune effect, because memory T cells will not be depleted.
CD137 is very attractive as an immune tumor target, and according to existing clinical data, it is still one of the most promising targets among T cell co-stimulatory receptors in TNFRSF. At present, the first phase of research on the next generation of CD137 targeting molecules is dedicated to solving the problem of liver toxicity without affecting the efficacy of the drug.
Understanding the biological characteristics of patients treated with CD137 and the strategy of selecting patients to optimize clinical response are critical to the future success of CD137-targeted drugs. The CD137 double antibody and its combination therapy will open up a new path for tumor immunotherapy.
(source:internet, reference only)