Development of CDX-1140, an agonist CD40 antibody for cancer immunotherapy

Vitale, Laura; Thomas, Lawrence J.; He, Lizhen; O’Neill, Thomas; Widger, Jenifer; Crocker, Andrea; Sundarapandiyan, Karuna; Storey, James R.; Forsberg, Eric M.; Weidlick, Jeffrey; Baronas, April R.; Gergel, Lauren E.; Boyer, James M.; Sisson, Crystal; Goldstein, J.; Marsh, Henry C.; Keler, Tibor

doi:10.1007/s00262-018-2267-0

Cited by 42 publications

(53 citation statements)

References 38 publications

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“…CDX-1140, developed by Celldex Therapeutics, Inc., is a human IgG2 antibody that stimulates CD40 signalling without the requirement for cross-linking or Fc receptor interactions ( 85 ). This drug is currently being investigated in a phase I clinical trial.…”

Section: Other Agonistic Cd40 Antibodiesmentioning

confidence: 99%

Characteristics and clinical trial results of agonistic anti‑CD40 antibodies in the treatment of malignancies (Review)

Wang

2020

Oncol Lett

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Cluster of differentiation 40 (CD40) mediates many immune activities. Preclinical studies have shown that activation of CD40 can evoke massive antineoplastic effects in several tumour models in vivo, providing a rationale for using CD40 agonists in cancer immunotherapy. To date, several potential agonistic antibodies that target CD40 have been investigated in clinical trials. Early clinical trials have shown that the adverse events associated with agonists of CD40 thus far have been largely transient and clinically controllable, including storms of cytokine release, hepatotoxicity and thromboembolic events. An antitumour effect of targeting CD40 for monotherapy or combination therapy has been observed in some tumours. However, these antitumour effects have been moderate. The present review aimed to provide updated details of the clinical results of these agonists, and offer information to further investigate the strategies of combining CD40 activation with chemotherapy, radiotherapy, targeted therapy and immunomodulators. Furthermore, biomarkers should be identified for monitoring and predicting responses and informing resistance mechanisms. Contents 1. Introduction 2. The structure of CD40/CD40L 3. The physiological role of CD40/CD40L 4. The role of the CD40/CD40L pathway in malignancy 5. The profiles of agonistic antibodies targeting CD40 for cancer therapy 6. Clinical trials of anti-CD40 mAbs for treating the malignancies 7. Other agonistic CD40 antibodies 8. Safety and clinical tolerability of anti-CD40 agonistic antibodies 9. Conclusion and outlook

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Section: Other Agonistic Cd40 Antibodiesmentioning

confidence: 99%

Characteristics and clinical trial results of agonistic anti‑CD40 antibodies in the treatment of malignancies (Review)

Wang

2020

Oncol Lett

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“…The nonoverlapping roles of CD47/SIRPa and CD40/CD40L in bridging innate and adaptive cancer immunotherapy suggests that these two pathways could be complimentary or synergistic in combination. SIRPa-Fc fusion proteins, CD40L-Fc fusion proteins, and CD40 agonist antibodies have been successfully used as therapeutics (21)(22)(23)(24)(25)(26)(27)(28). The extracellular domains (ECD) of PD-1 and OX40L can be adjoined via an Fc domain (PD-1-Fc-OX40L), leading to superior therapeutic properties compared with anti-PD-1 and anti-OX40 combinations (29).…”

Section: Introductionmentioning

confidence: 99%

CD40 Enhances Type I Interferon Responses Downstream of CD47 Blockade, Bridging Innate and Adaptive Immunity

Silva

Fromm

Shuptrine

et al. 2020

Cancer Immunology Research

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Disrupting the binding of CD47 to SIRPa has emerged as a promising immunotherapeutic strategy for advanced cancers by potentiating antibody-dependent cellular phagocytosis (ADCP) of targeted antibodies. Preclinically, CD47/SIRPa blockade induces antitumor activity by increasing the phagocytosis of tumor cells by macrophages and enhancing the cross-presentation of tumor antigens to CD8 þ T cells by dendritic cells; both of these processes are potentiated by CD40 signaling. Here we generated a novel, two-sided fusion protein incorporating the extracellular domains of SIRPa and CD40L, adjoined by a central Fc domain, termed SIRPa-Fc-CD40L. SIRPa-Fc-CD40L bound CD47 and CD40 with high affinity and activated CD40 signaling in the absence of Fc receptor cross-linking. No evidence of hemolysis, hemagglutination, or thrombocytopenia was observed in vitro or in cynomolgus macaques. Murine SIRPa-Fc-CD40L outperformed CD47 blocking and CD40 agonist antibodies in murine CT26 tumor models and synergized with immune checkpoint blockade of PD-1 and CTLA4. SIRPa-Fc-CD40L activated a type I interferon response in macrophages and potentiated the activity of ADCP-competent targeted antibodies both in vitro and in vivo. These data illustrated that whereas CD47/SIRPa inhibition could potentiate tumor cell phagocytosis, CD40-mediated activation of a type I interferon response provided a bridge between macrophage-and T-cell-mediated immunity that significantly enhanced durable tumor control and rejection.

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“…23,24,53 Further, the CD40 antibody CDX-1140 in IgG2 subclass has superior Fc-independent agonist activity than its IgG1 counterpart. 54 Recently, it has been demonstrated that EGFR-specific IgG2 can induce CDC and ADCC. 55 This underlines the necessity of using Fc mutations to reduce FcγR interaction also for this supposedly less Fccompetent IgG subclass.…”

Section: Discussionmentioning

confidence: 99%

Influence of the bispecific antibody IgG subclass on T cell redirection

Kapelski

Cleiren

Attar

et al. 2019

mAbs

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T cell redirection mediated by bispecific antibodies (BsAbs) is a promising cancer therapy. Dual antigen binding is necessary for potent T cell redirection and is influenced by the structural characteristics of a BsAb, which are dependent on its IgG subclass. In this study, model BsAbs targeting CD19xCD3 were generated in variants of IgG1, IgG2, and IgG4 carrying Fc mutations that reduce FcγR interaction, and two chimeric IgG subclasses termed IgG1:2 and IgG4:2, in which the IgG1-or IgG4-F(ab) 2 are grafted on an IgG2 Fc. Molecules containing an IgG2 or IgG4-F(ab) 2 domain were confirmed to be the most structurally compact molecules. All BsAbs were shown to bind both of their target proteins (and corresponding cells) equally well. However, CD19xCD3 IgG2 did not bind both antigens simultaneously as measured by the absence of cellular clustering of T cells with target cells. This translated to a reduced potency of IgG2 BsAbs in T-cell redirection assays. The activity of IgG2 BsAbs was fully restored in the chimeric subclasses IgG4:2 and IgG1:2. This confirmed the major contribution of the F(ab) 2 region to the BsAb's functional activity and demonstrated that function of BsAbs can be modulated by engineering molecules combining different Fc and F(ab) 2 domains.

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Development of CDX-1140, an agonist CD40 antibody for cancer immunotherapy

Cited by 42 publications

References 38 publications

Characteristics and clinical trial results of agonistic anti‑CD40 antibodies in the treatment of malignancies (Review)

Characteristics and clinical trial results of agonistic anti‑CD40 antibodies in the treatment of malignancies (Review)

CD40 Enhances Type I Interferon Responses Downstream of CD47 Blockade, Bridging Innate and Adaptive Immunity

Influence of the bispecific antibody IgG subclass on T cell redirection

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