A Bispecific Molecule Targeting CD40 and Tumor Antigen Mesothelin Enhances Tumor-Specific Immunity

Ye, Shiming; Cohen, Diane; Belmar, Nicole A.; Choi, Donghee; Tan, Siu Sze; Sho, Mien; Akamatsu, Yoshiko; Kim, Han; Iyer, Ramesh; Cabel, Jeanne M; Lake, Marc; Song, Danying; Harlan, John E.; Zhang, Catherine; Fang, Yuni; Wahl, Alan F.; Culp, Patricia; Hollenbaugh, Diane; Chao, Debra T.

doi:10.1158/2326-6066.cir-18-0805

Cited by 36 publications

(29 citation statements)

References 43 publications

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“…6 Such approaches will need to consider variations in circulating MDSC frequencies and mechanism of agonist activity either by drug design or patient selection. Some approaches, including tumor-targeted CD40 agonists, are showing promise in preclinical models, 23 yet their relative safety versus efficacy profiles are yet to be determined. 24…”

Section: Discussionmentioning

confidence: 99%

CD40 agonist-induced IL-12p40 potentiates hepatotoxicity

Bonnans

Thomas

et al. 2020

J Immunother Cancer

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BackgroundCD40 is a compelling target for cancer immunotherapy, however, attempts to successfully target this pathway have consistently been hampered by dose-limiting toxicity issues in the clinic that prevents the administration of efficacious doses.MethodsHere, using cytokine and cytokine receptor depletion strategies in conjunction with a potent CD40 agonist, we investigated mechanisms underlying the two primary sources of CD40 agonist-associated toxicity, hepatotoxicity and cytokine release syndrome (CRS).ResultsWe demonstrate that CD40 agonist -induced hepatotoxicity and CRS are mechanistically independent. Historical data have supported a role for interleukin-6 (IL-6) in CRS-associated wasting, however, our findings instead show that an inflammatory cytokine network involving TNF, IL-12p40, and IFNγ underlie this process. Deficiency of TNF or IFNγ did not influence CD40-induced hepatitis however loss of IL-12p40 significantly decreased circulating concentrations of liver enzymes and reduced the frequency of activated CD14+MHCII+myeloid cells in the liver, indicating a role for IL-12p40 in liver pathology.ConclusionsAs clinical research programs aim to circumnavigate toxicity concerns while maintaining antitumor efficacy it will be essential to understand which features of CD40 biology mediate antitumor function to develop both safe and efficacious agonists.

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Section: Discussionmentioning

confidence: 99%

CD40 agonist-induced IL-12p40 potentiates hepatotoxicity

Bonnans

Thomas

et al. 2020

J Immunother Cancer

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“…For example, Bano and colleagues generated a Fab-like bsAb targeting MSLN and FCγRIII (CD16) that is expressed by natural killer cells [1]. Similarly, Ye and colleagues constructed bsAbs containing single-chain Fv domains against MSLN and CD40 [46]; to avoid systemic toxicity, their bsAbs had agonistic anti-CD40 activity. Notably, by limiting the antigen sink effect of CD3 in the periphery, MG1122-B was designed as an MSLN-targeting, T-cell-engaging bsAb with low systemic toxicity.…”

Section: Discussionmentioning

confidence: 99%

A Novel T Cell-Engaging Bispecific Antibody for Treating Mesothelin-Positive Solid Tumors

Yoon¹,

Lee²,

Lee³

et al. 2020

Biomolecules

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As mesothelin is overexpressed in various types of cancer, it is an attractive target for therapeutic antibodies. T-cell bispecific antibodies bind to target cells and engage T cells via binding to CD3, resulting in target cell killing by T-cell activation. However, the affinity of the CD3-binding arm may influence CD3-mediated plasma clearance or antibody trapping in T-cell-containing tissues. This may then affect the biodistribution of bispecific antibodies. In this study, we used scFab and knob-into-hole technologies to construct novel IgG-based 1 + 1 MG1122-A and 2 + 1 MG1122-B bispecific antibodies against mesothelin and CD3ε. MG1122-B was designed to be bivalent to mesothelin and monovalent to CD3ε, using a 2 + 1 head-to-tail format. Activities of the two antibodies were evaluated in mesothelin-positive tumor cells in vitro and xenograft models in vivo. Although both antibodies exhibited target cell killing efficacy and produced regression of xenograft tumors with CD8+ T-cell infiltration, the antitumor efficacy of MG1122-B was significantly higher. MG1122-B may improve tumor targeting because of its bivalency for tumor antigen. It may also reduce systemic toxicity by limiting the activation of circulating T cells. Thus, MG1122-B may be useful for treating mesothelin-positive solid tumors.

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“…found that local delivery and slow release of agonistic anti-CD40 Ab to the tumor-draining area can effectively activate local tumor-specific CD8 T cells to become systemic effectors without systemic toxicity or non-specific CTL activation (32). And recent studies demonstrate that it's possible to engineer a tumor-targeted CD40 molecule by conjugating a CD40 agonist mAb chemically with a tumor-homing peptide could potentially maximize antitumor potency while limiting systemic toxicity in clinical studies (33,34). Therefore, it's necessary to explore the effect of these routes on HPV-specific Tscm cells and their safety in clinical studies.…”

Section: Discussionmentioning

confidence: 99%

CD40 Accelerates the Antigen-Specific Stem-Like Memory CD8+ T Cells Formation and Human Papilloma Virus (HPV)-Positive Tumor Eradication

et al. 2020

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Antigen-specific stem-like memory CD8 + T cells (Tscm) have a series of stem cell characteristics, including long-term survival, self-renewal, anti-apoptosis and persistent differentiation into cytotoxic T cells. The effective induction of tumor-specific CD8 + Tscm could persistently eradicate tumor in pro-tumor hostile microenvironment. This study was to investigate the role of CD40 in HPV16-specific CD8 + Tscm induction and its anti-tumor function. We found that CD40 activation accelerated vaccine-induced HPV16 E7-specific CD8 + Tscm formation. Comparing to other HPV-specific CD8 + T cells, CD8 + Tscm were found to be stronger and long-term anti-tumor function, in vivo and in vitro, even in the adoptive cellular transferring model. Furthermore, high frequencies of Tscm might prevent the HPV infection to move on to the development of cancer. And the CD40 effect on Tscm involved Wnt/β-catenin activation. Our study suggest that CD40 activation supports the generation of tumor-specific CD8 + Tscm, thus providing new insight into cancer immunotherapy.

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A Bispecific Molecule Targeting CD40 and Tumor Antigen Mesothelin Enhances Tumor-Specific Immunity

Cited by 36 publications

References 43 publications

CD40 agonist-induced IL-12p40 potentiates hepatotoxicity

CD40 agonist-induced IL-12p40 potentiates hepatotoxicity

A Novel T Cell-Engaging Bispecific Antibody for Treating Mesothelin-Positive Solid Tumors

CD40 Accelerates the Antigen-Specific Stem-Like Memory CD8+ T Cells Formation and Human Papilloma Virus (HPV)-Positive Tumor Eradication

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