Rationale and clinical development of CD40 agonistic antibodies for cancer immunotherapy

Smith, Karin Enell; Deronic, Adnan; Hägerbrand, Karin; Norlén, Per; Ellmark, Peter

doi:10.1080/14712598.2021.1934446

Cited by 17 publications

(4 citation statements)

References 158 publications

(221 reference statements)

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“…Evidence of clinical benefit of immunotherapy with agonistic CD40 antibodies as single agents or in combination with chemotherapy or ICI are emerging 16 17 and several second generation CD40 agonists are in clinical development. 16 Development of third generation CD40 targeting therapies either as bispecific antibodies (bsAbs) or fusion proteins is currently underway. 18 19 A novel approach called Neo-X-Prime has been developed by us and aims to increase the efficacy of CD40-targeting therapies.…”

Section: Introductionmentioning

confidence: 99%

Bispecific antibodies targeting CD40 and tumor-associated antigens promote cross-priming of T cells resulting in an antitumor response superior to monospecific antibodies

Hägerbrand

Varas

Deronic

et al. 2022

J Immunother Cancer

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BackgroundIndications with poor T-cell infiltration or deficiencies in T-cell priming and associated unresponsiveness to established immunotherapies represent an unmet medical need in oncology. CD40-targeting therapies designed to enhance antigen presentation, generate new tumor-specific T cells, and activate tumor-infiltrating myeloid cells to remodel the tumor microenvironment, represent a promising opportunity to meet this need. In this study, we present the first in vivo data supporting a role for tumor-associated antigen (TAA)-mediated uptake and cross-presentation of tumor antigens to enhance tumor-specific T-cell priming using CD40×TAA bispecific antibodies, a concept we named Neo-X-Prime.MethodsBispecific antibodies targeting CD40 and either of two cell-surface expressed TAA, carcinoembryonic antigen-related cell adhesion molecule 5 (CEA) or epithelial cell adhesion molecule (EpCAM), were developed in a tetravalent format. TAA-conditional CD40 agonism, activation of tumor-infiltrating immune cells, antitumor efficacy and the role of delivery of tumor-derived material such as extracellular vesicles, tumor debris and exosomes by the CD40×TAA bispecific antibodies were demonstrated in vitro using primary human and murine cells and in vivo using human CD40 transgenic mice with different tumor models.ResultsThe results showed that the CD40×TAA bispecific antibodies induced TAA-conditional CD40 activation both in vitro and in vivo. Further, it was demonstrated in vitro that they induced clustering of tumor debris and CD40-expressing cells in a dose-dependent manner and superior T-cell priming when added to dendritic cells (DC), ovalbumin (OVA)-specific T cells and OVA-containing tumor debris or exosomes. The antitumor activity of the Neo-X-Prime bispecific antibodies was demonstrated to be significantly superior to the monospecific CD40 antibody, and the resulting T-cell dependent antitumor immunity was directed to tumor antigens other than the TAA used for targeting (EpCAM).ConclusionsThe data presented herein support the hypothesis that CD40×TAA bispecific antibodies can engage tumor-derived vesicles containing tumor neoantigens to myeloid cells such as DCs resulting in an improved DC-mediated cross-priming of tumor-specific CD8+T cells. Thus, this principle may offer therapeutics strategies to enhance tumor-specific T-cell immunity and associated clinical benefit in indications characterized by poor T-cell infiltration or deficiencies in T-cell priming.

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Section: Introductionmentioning

confidence: 99%

Bispecific antibodies targeting CD40 and tumor-associated antigens promote cross-priming of T cells resulting in an antitumor response superior to monospecific antibodies

Hägerbrand

Varas

Deronic

et al. 2022

J Immunother Cancer

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“…S 9 ). For CD40, there was no apparent correlation between a given antibody’s activity in the different formats (WT IgG, IgG2 C131S, iAb aff1 ) and its previously reported epitope 28 – 31 . However, the strongest agonist activity was observed for iAb aff1 formats of ravagalimab, dacetuzumab, giloralimab, and sotigolimab (Fig.…”

Section: Resultsmentioning

confidence: 80%

i-shaped antibody engineering enables conformational tuning of biotherapeutic receptor agonists

Romei,

Leonard,

Katz

et al. 2024

Nat Commun

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The ability to leverage antibodies to agonize disease relevant biological pathways has tremendous potential for clinical investigation. Yet while antibodies have been successful as antagonists, immune mediators, and targeting agents, they are not readily effective at recapitulating the biology of natural ligands. Among the important determinants of antibody agonist activity is the geometry of target receptor engagement. Here, we describe an engineering approach inspired by a naturally occurring Fab-Fab homotypic interaction that constrains IgG in a unique i-shaped conformation. i-shaped antibody (iAb) engineering enables potent intrinsic agonism of five tumor necrosis factor receptor superfamily (TNFRSF) targets. When applied to bispecific antibodies against the heterodimeric IL-2 receptor pair, constrained bispecific IgG formats recapitulate IL-2 agonist activity. iAb engineering provides a tool to tune agonist antibody function and this work provides a framework for the development of intrinsic antibody agonists with the potential for generalization across broad receptor classes.

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“…As a consequence, CD40 signaling licenses APCs for the stimulation of antigen-specific CD8 T-cell responses by the upregulation of costimulatory surface receptors and the release of T-cell-activating cytokines [ 3 ]. The therapeutic triggering of canonical CD40 signaling is particularly attractive, since it provides an opportunity to elicit novel patient- and tumor-specific immune responses using a conventional biological, e.g., an agonistic antibody [ 4 , 5 ]. Experiments in mice have provided extensive support for this therapeutic strategy.…”

Section: Introductionmentioning

confidence: 99%

Fcγ-Receptor-Independent Controlled Activation of CD40 Canonical Signaling by Novel Therapeutic Antibodies for Cancer Therapy

Beckmann,

Reitinger,

Yan

et al. 2024

Antibodies

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The activation of CD40-mediated signaling in antigen-presenting cells is a promising therapeutic strategy to promote immune responses against tumors. Most agonistic anti-CD40 antibodies currently in development require the Fcγ-receptor (FcγR)-mediated crosslinking of CD40 molecules for a meaningful activation of CD40 signaling but have limitations due to dose-limiting toxicities. Here we describe the identification of CD40 antibodies which strongly stimulate antigen-presenting cells in an entirely FcγR-independent manner. These Fc-silenced anti-CD40 antibodies induce an efficient upregulation of costimulatory receptors and cytokine release by dendritic cells. Finally, the most active identified anti-CD40 antibody shows activity in humanized mice. More importantly, there are no signs of obvious toxicities. These studies thus demonstrate the potent activation of antigen-presenting cells with anti-CD40 antibodies lacking FcγR-binding activity and open the possibility for an efficacious and safe combination therapy for cancer patients.

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Rationale and clinical development of CD40 agonistic antibodies for cancer immunotherapy

Cited by 17 publications

References 158 publications

Bispecific antibodies targeting CD40 and tumor-associated antigens promote cross-priming of T cells resulting in an antitumor response superior to monospecific antibodies

Bispecific antibodies targeting CD40 and tumor-associated antigens promote cross-priming of T cells resulting in an antitumor response superior to monospecific antibodies

i-shaped antibody engineering enables conformational tuning of biotherapeutic receptor agonists

Fcγ-Receptor-Independent Controlled Activation of CD40 Canonical Signaling by Novel Therapeutic Antibodies for Cancer Therapy

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