A phase 1 study of intravenous mitazalimab, a CD40 agonistic monoclonal antibody, in patients with advanced solid tumors

Moreno, Víctor; Perets, Ruth; Peretz-Yablonski, T.; Fourneau, Nele; Girgis, Suzette; Guo, Yuxin; Hellemans, Peter; Verona, Raluca; Pendás, Natalia; Xia, Qianghua; Geva, Ravit; Calvo, Emiliano

doi:10.1007/s10637-022-01319-2

Cited by 14 publications

(21 citation statements)

References 28 publications

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Section: Discussionmentioning

confidence: 99%

“…Consequently, this study only investigated one administration of the iSRB-loaded anti-CD40 implant subcutaneously in mice, and did not investigate the impact of adding one fraction of low-dose radiation or intravenous injection of anti-CD40 to compare their associated toxicity. However, numerous studies have investigated the associated toxicity generated from systemic treatment with an agonistic anti-CD40 preclinically or clinically [34,35] Standard variations in rodents' clinical chemistry [36] and hematology [37] parameters transpire due to multiple effects, including the strain, age, gender, nutrition, restriction, anesthesia, day-to-day effects, lodging method, dormant infections, blood collection hemorrhage site, and handling methods [38]. These mentioned features contribute significantly to the obtained outcomes.…”

Section: Discussionmentioning

confidence: 99%

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Pre-Clinical Investigations of the Pharmacodynamics of Immunogenic Smart Radiotherapy Biomaterials (iSRB)

Moreau,

Acter,

Ngema

et al. 2023

Pharmaceutics

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The use of an immunogenic smart radiotherapy biomaterial (iSRB) for the delivery of anti-CD40 is effective in treating different cancers in animal models. This study further characterizes the use of iSRBs to evaluate any associated toxicity in healthy C57BL6 mice. iSRBs were fabricated using a poly-lactic-co-glycolic-acid (PLGA) polymer mixed with titanium dioxide (TiO2) nanoparticles incorporated into its matrix. Animal studies included investigations of freely injected anti-CD40, anti-CD40-loaded iSRBs, unloaded iSRBs and control (healthy) animal cohorts. Mice were euthanized at pre-determined time points post-treatment to evaluate the serum chemistry pertaining to kidney and liver toxicity and cell blood count parameters, as well as pathology reports on organs of interest. Results showed comparable liver and kidney function in all cohorts. The results indicate that using iSRBs with or without anti-CD40 does not result in any significant toxicity compared to healthy untreated animals. The findings provide a useful reference for further studies aimed at optimizing the therapeutic efficacy and safety of iSRBs and further clinical translation work.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Pre-Clinical Investigations of the Pharmacodynamics of Immunogenic Smart Radiotherapy Biomaterials (iSRB)

Moreau,

Acter,

Ngema

et al. 2023

Pharmaceutics

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“…Recently, mitazalimumab, a fully humanised agonistic CD40 IgG1 (alias: ADC1013) has been shown to encompass a manageable safety profile among 95 patients with advanced solid tumours, unfortunately not including any PLC patients. Only 1 out of 95 patients (RCC) experienced partial response ( 191 ). These data have pleaded for identifying patients that are sensitive to CD40 engagement and again argue for combining CD40 agonistic antibodies with other regimen to enhance clinical activity.…”

Section: Co-stimulatory Immune Checkpoints Are Widely Expressed Among...mentioning

confidence: 99%

Engaging stimulatory immune checkpoint interactions in the tumour immune microenvironment of primary liver cancers – how to push the gas after having released the brake

Rakké,

Buschow,

IJzermans

et al. 2024

Front. Immunol.

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Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) are the first and second most common primary liver cancer (PLC). For decades, systemic therapies consisting of tyrosine kinase inhibitors (TKIs) or chemotherapy have formed the cornerstone of treating advanced-stage HCC and CCA, respectively. More recently, immunotherapy using immune checkpoint inhibition (ICI) has shown anti-tumour reactivity in some patients. The combination regimen of anti-PD-L1 and anti-VEGF antibodies has been approved as new first-line treatment of advanced-stage HCC. Furthermore, gemcibatine plus cisplatin (GEMCIS) with an anti-PD-L1 antibody is awaiting global approval for the treatment of advanced-stage CCA. As effective anti-tumour reactivity using ICI is achieved in a minor subset of both HCC and CCA patients only, alternative immune strategies to sensitise the tumour microenvironment of PLC are waited for. Here we discuss immune checkpoint stimulation (ICS) as additional tool to enhance anti-tumour reactivity. Up-to-date information on the clinical application of ICS in onco-immunology is provided. This review provides a rationale of the application of next-generation ICS either alone or in combination regimen to potentially enhance anti-tumour reactivity in PLC patients.

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“…Neither study reported corresponding changes in the actual numbers of the T cell subsets that stained positive for Ki67 expression. A phase 1 study tested mitazalimab across a dose range of 0.075-1.2 mg/kg in patients with advanced solid tumors ( 46 ), and reported a broader range of pharmacodynamic findings ( 47 ). Specifically, deep and rapid declines in the number of B cells in the peripheral blood were reported following the first dose, which was attributed to migration of B cells which are known to express CD40, and presumed to be bound by mitazalimab.…”

Section: Clinical Data From Trials Testing Bivalent Tnfr Agonist Biva...mentioning

confidence: 99%

“…Aside from the unusual bell-shaped dose response properties of TNFR agonist antibodies in humans, development of many agents has been hampered due to the emergence of dose-dependent toxicities, principally in the form of liver toxicity or cytokine release syndrome - particularly for CD40 and 41BB agonist antibodies. Liver toxicities and/or cytokine release syndrome have been reported from phase 1 clinical trials of selicrelumab, sotigalimab, mitazalimab, ChiLob7/4, and urelumab, which occurred at doses below 0.5 mg/kg, and were partially mitigated by pre-medication with corticosteroids ( 8 , 25 , 26 , 47 , 53 – 55 ). Another 41BB agonist antibody, utomilumab, was not found to cause liver enzyme elevations nor cytokine release syndrome, however the highest dose tested was 0.3 mg/kg and no evidence of agonist activity was reported in humans ( 25 ).…”

Section: Clinical Data From Trials Testing Bivalent Tnfr Agonist Biva...mentioning

confidence: 99%

Reconciling intrinsic properties of activating TNF receptors by native ligands versus synthetic agonists

Fromm,

de Silva,

Schreiber

2023

Front. Immunol.

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The extracellular domain of tumor necrosis factor receptors (TNFR) generally require assembly into a homotrimeric quaternary structure as a prerequisite for initiation of signaling via the cytoplasmic domains. TNF receptor homotrimers are natively activated by similarly homo-trimerized TNF ligands, but can also be activated by synthetic agonists including engineered antibodies and Fc-ligand fusion proteins. A large body of literature from pre-clinical models supports the hypothesis that synthetic agonists targeting a diverse range of TNF receptors (including 4-1BB, CD40, OX40, GITR, DR5, TNFRSF25, HVEM, LTβR, CD27, and CD30) could amplify immune responses to provide clinical benefit in patients with infectious diseases or cancer. Unfortunately, however, the pre-clinical attributes of synthetic TNF receptor agonists have not translated well in human clinical studies, and have instead raised fundamental questions regarding the intrinsic biology of TNF receptors. Clinical observations of bell-shaped dose response curves have led some to hypothesize that TNF receptor overstimulation is possible and can lead to anergy and/or activation induced cell death of target cells. Safety issues including liver toxicity and cytokine release syndrome have also been observed in humans, raising questions as to whether those toxicities are driven by overstimulation of the targeted TNF receptor, a non-TNF receptor related attribute of the synthetic agonist, or both. Together, these clinical findings have limited the development of many TNF receptor agonists, and may have prevented generation of clinical data which reflects the full potential of TNF receptor agonism. A number of recent studies have provided structural insights into how different TNF receptor agonists bind and cluster TNF receptors, and these insights aid in deconvoluting the intrinsic biology of TNF receptors with the mechanistic underpinnings of synthetic TNF receptor agonist therapeutics.

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A phase 1 study of intravenous mitazalimab, a CD40 agonistic monoclonal antibody, in patients with advanced solid tumors

Cited by 14 publications

References 28 publications

Pre-Clinical Investigations of the Pharmacodynamics of Immunogenic Smart Radiotherapy Biomaterials (iSRB)

Pre-Clinical Investigations of the Pharmacodynamics of Immunogenic Smart Radiotherapy Biomaterials (iSRB)

Engaging stimulatory immune checkpoint interactions in the tumour immune microenvironment of primary liver cancers – how to push the gas after having released the brake

Reconciling intrinsic properties of activating TNF receptors by native ligands versus synthetic agonists

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