Abstract 555: A novel human TNFR2 antibody (MM-401) modulates T cell responses in anti-cancer immunity

Sampson, James F.; Kurella, Vinodh; Paragas, Violette; Kumar, Sandeep; Lulo, James; Qiu, James; Razlog, Maja; Fulton, Ross B.; Camblin, Adam J.; Richards, Jennifer; Wong, Christina S.F.; Koshkaryev, Alexander; Suchy, James; Grabow, Stephanie; Muda, Marco; Raue, Andreas; Drummond, Daryl C.; Tam, Eric

doi:10.1158/1538-7445.sabcs18-555

Cited by 3 publications

(9 citation statements)

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“…56,89,[179][180][181][182] However, agonistic TNFR2 antibodies (Y9, and MM-401) were potent anti-tumor activity in different humanized mouse models. 159,[183][184][185][186] Furthermore, Y9 treatment alone elicits more potent anti-tumor activity than the treatment with anti-PD-1 alone in the WEHI-164 model, while a combination of both (Y9+anti-PD-1) showed greater survival in CT26 and EMT6 syngeneic mice tumor models. 159 Interestingly, the activity of Y9 did not depend on TNFR2 expression on tumor cells or the depletion of Treg cells.…”

Section: Tnfr2 Antagonistic Antibodymentioning

confidence: 99%

“…159,183 MM-401, a humanized agonistic anti-TNFR2 antibody that promoted antitumor immunity in vitro via induction antibody-dependent cellular cytotoxicity (ADCC). [184][185][186] It is reported that after the treatment with MM-401, the number of Treg cells in human ovarian cancer ascites is reduced. 184,186 As TNFR2 agonists appear to have both anti-tumor and anti-inflammatory effects, future studies can reconcile these seemingly opposite effects.…”

Section: Tnfr2 Antagonistic Antibodymentioning

confidence: 99%

“…[184][185][186] It is reported that after the treatment with MM-401, the number of Treg cells in human ovarian cancer ascites is reduced. 184,186 As TNFR2 agonists appear to have both anti-tumor and anti-inflammatory effects, future studies can reconcile these seemingly opposite effects. eliminating Treg activity, or stimulating the activation of CD8 + CTLs, respectively.…”

Section: Tnfr2 Antagonistic Antibodymentioning

confidence: 99%

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TNFR2: Role in Cancer Immunology and Immunotherapy

Yang¹,

Islam²,

Hu³

et al. 2021

ITT

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Immune checkpoint inhibitors (ICIs), including anti-CTLA-4 (cytotoxic T lymphocyte antigen-4) and anti-PD-1/PD-L1 (programmed death-1/programmed death-ligand 1), represent a turning point in the cancer immunotherapy. However, only a minor fraction of patients could derive benefit from such therapy. Therefore, new strategies targeting additional immune regulatory mechanisms are urgently needed. CD4 + Foxp3 + regulatory T cells (Tregs) represent a major cellular mechanism in cancer immune evasion. There is compelling evidence that tumor necrosis factor (TNF) receptor type II (TNFR2) plays a decisive role in the activation and expansion of Tregs and other types of immunosuppressive cells such as myeloid-derived suppressor cells (MDSCs). Furthermore, TNFR2 is also expressed by some tumor cells. Emerging experimental evidence indicates that TNFR2 may be a therapeutic target to enhance naturally occurring or immunotherapeutic-triggered anti-tumor immune responses. In this article, we discuss recent advances in the understanding of the mechanistic basis underlying the Treg-boosting effect of TNFR2. The role of TNFR2-expressing highly suppressive Tregs in tumor immune evasion and their possible contribution to the non-responsiveness to checkpoint treatment are analyzed. Moreover, the role of TNFR2 expression on tumor cells and the impact of TNFR2 signaling on other types of cells that shape the immunological landscape in the tumor microenvironment, such as MDSCs, MSCs, ECs, EPCs, CD8 + CTLs, and NK cells, are also discussed. The reports revealing the effect of TNFR2-targeting pharmacological agents in the experimental cancer immunotherapy are summarized. We also discuss the potential opportunities and challenges for TNFR2-targeting immunotherapy.

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Section: Tnfr2 Antagonistic Antibodymentioning

confidence: 99%

Section: Tnfr2 Antagonistic Antibodymentioning

confidence: 99%

Section: Tnfr2 Antagonistic Antibodymentioning

confidence: 99%

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TNFR2: Role in Cancer Immunology and Immunotherapy

Yang¹,

Islam²,

Hu³

et al. 2021

ITT

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“…[77,[78][79][80][81][82]. In separate humanized mouse models, Moreover, agonistic TNFR2 antibodies had substantial anti-tumor action [83][84][85][86][87]. Furthermore, in the WEHI-164 model, the Y9 therapy alone elicits more robust anti-tumor activity than anti-PD-1 treatment alone.…”

Section: Clinically Administrated Anti Tnfr2 Agonistsmentioning

confidence: 99%

“…The quantity of Treg cells in human ovarian cancer ascites has been observed to decrease following treatment with MM-401. [85,87]. Future research can reconcile these seemingly opposing effects because TNFR2 agonists appear to have both anti-tumor and anti-inflammatory properties.…”

Section: Mm-401mentioning

confidence: 99%

TNFR2 Antagonist and Agonist: A Potential Therapeutics in Cancer Immunotherapy

Quazi¹

2021

Preprint

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Tumor necrosis factor receptor 2 or TNFR2 is considered as an appealing target protein due its limited frequency to Tregs which are highly immunosuppressive and its presence on human malignancies. Numerous studies have revealed that TNFR2 is primarily found on MDSCs (myeloid derived suppressor cells) and CD+Foxp3+ regulatory T cell (Tregs). It has a great importance in the proliferation and functional activity of Tregs and MDSCs. To treat malignancies and diseases like autoimmune disorder, the suppressor activity of TNFR2 must be eliminated by downregulation or upregulation. Therefore, at the molecular level, advances in comprehension of TNFR2's complex structure and its binding to TNF have opened the door to structure-guided drug development. Two key obstacles of cancer treatment are the dearth of Treg-specific inhibitors and the lack of widely applicable ways to directly target tumors via frequently expressed surface oncogenes. Many researchers have discovered potential antagonist and agonist of TNFR2 which were successful in the inhibition of Tregs proliferation, reduction of soluble TNFR2 secretion from normal cells and in the expansion of T effector cells. The representation of the data in the following review article elucidates the clinically administrated TNFR2 antagonist and agonist in the treatment of cancers.

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Antibody-based approaches to modulate immune response

Cisteró¹

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In context of an increasing interest in immunotherapeutic treatments, the work described in this thesis expands the current knowledge of several potential antibody-based therapeutic approaches. A new development is the use of bispecific antibodies (BsAb). To introduce BsAb, chapter 2 describes the different platforms currently used to generate IgG-like and non-IgG-like BsAbs, as well as the strategies to gain clinical approval for the different BsAbs. A highly selective binding, as can be achieved with BsAbs, could be beneficial to ‘target’ certain cell populations, such as Tregs, against which current treatments appear to be insufficiently specific. Focusing on BsAb-based therapeutic approaches, in chapter 3 we investigate a novel strategy to optimize a T-cell redirecting bispecific antibody. Two Fab x sdAb-Fc, directed against CD3 and EGFR, with different lengths of the hinge region, were compared. The results show that a shorter hinge design improves BsAb-induced anti-tumor activity, induces more effector cell/target cell clustering and activates T cells more efficiently. In addition, we show (chapter 4) how important it is to select the right isotype antibody. In a mouse tumor model, only IgG2a antibodies were found to exert anti-tumor function, achieving a survival rate of approximately 50%. None of the isotypes tested showed a synergistic effect with adoptive T-cell therapy. An increasing interest in the costimulatory receptor TNFR2 in cancer has prompted us to design, generate and produce novel anti-mTNFR2 antibodies (chapter 5). The characterization and different features of these antibodies are described in this chapter, and they could be used as tools in follow-up studies to further investigate i) the role of TNFR2 in cancer, and ii) how TNFR2 targeting with different antibody candidates that either block or activate this receptor could improve immunotherapy. In chapter 6, two anti-mTNFR2 antibodies were selected for assessment of their application in vitro, ex vivo and in vivo, which revealed their capacity to bind to Tregs but also to CD4+ effector T cells. Taken together, the results presented in this thesis highlight the progress achieved in immunotherapy approaches, with focus on BsAbs and novel strategies to improve cancer treatments. Furthermore, novel anti-mTNFR2 antibodies were developed and featured as useful tools to unravel the role of this receptor in tumor growth.

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Abstract 555: A novel human TNFR2 antibody (MM-401) modulates T cell responses in anti-cancer immunity

Cited by 3 publications

References 0 publications

TNFR2: Role in Cancer Immunology and Immunotherapy

TNFR2: Role in Cancer Immunology and Immunotherapy

TNFR2 Antagonist and Agonist: A Potential Therapeutics in Cancer Immunotherapy

Antibody-based approaches to modulate immune response

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