CDX-1140, a Novel Agonist CD40 Antibody with Potent Anti-Lymphoma Activity

He, Lizhen; Testa, James; Wasiuk, Anna; Weidlick, Jeffery; Sisson, Crystal; Vitale, Laura; O’Neill, Thomas; Crocker, Andrea; Widger, Jenifer; Goldstein, J.; Marsh, Henry C.; Keler, Tibor

doi:10.1182/blood.v128.22.1848.1848

Cited by 7 publications

(9 citation statements)

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“…Maximizing the agonist efficacy and utility of clinical candidate anti-CD40 Abs typically involves affinity maturation of the H and L chain variable regions (9), enhancing cross-linking of the C region with FcR (15), and screening and, in the case of CD40L agonists, making multimeric forms to enhance receptor cross-linking (4,16). Screening can also include identifying potent agonists without any need for Fc interaction (17,18), which may be problematic for human platelet activation if FcgRIIA interaction is maintained (15). Agonistic anti-CD40 Abs can either bind to sites that overlap the CD40L-interacting region or may interact with a site distinct from its ligand-binding region (6,15,18,19).…”

mentioning

confidence: 99%

Anti-CD40 Antibodies Fused to CD40 Ligand Have Superagonist Properties

Ceglia

Zurawski

Bouteau

et al. 2021

The Journal of Immunology

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CD40 is a potent activating receptor within the TNFR family expressed on APCs of the immune system, and it regulates many aspects of B and T cell immunity via interaction with CD40 ligand (CD40L; CD154) expressed on the surface of activated T cells. Soluble CD40L and agonistic mAbs directed to CD40 are being explored as adjuvants in therapeutic or vaccination settings. Some anti-CD40 Abs can synergize with soluble monomeric CD40L. We show that direct fusion of CD40L to certain agonistic anti-CD40 Abs confers superagonist properties, reducing the dose required for efficacy, notably greatly increasing total cytokine secretion by human dendritic cells. The tetravalent configuration of anti-CD40–CD40L Abs promotes CD40 cell surface clustering and internalization and is the likely mechanism of increased receptor activation. CD40L fused to either the L or H chain C termini, with or without flexible linkers, were all superagonists with greater potency than CD40L trimer. The increased anti-CD40–CD40L Ab potency was independent of higher order aggregation. Moreover, the anti-CD40–CD40L Ab showed higher potency in vivo in human CD40 transgenic mice compared with the parental anti-CD40 Ab. To broaden the concept of fusing agonistic Ab to natural ligand, we fused OX40L to an agonistic OX40 Ab, and this resulted in dramatically increased efficacy for proliferation and cytokine production of activated human CD4+ T cells as well as releasing the Ab from dependency on cross-linking. This work shows that directly fusing antireceptor Abs to ligand is a useful strategy to dramatically increase agonist potency.

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mentioning

confidence: 99%

Anti-CD40 Antibodies Fused to CD40 Ligand Have Superagonist Properties

Ceglia

Zurawski

Bouteau

et al. 2021

The Journal of Immunology

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“…Preclinical data showed an enhanced DC and B cell activation by CDX-1140, which synergizes with recombinant CD40L to enhance the agonist activity [206]. While xenografts models using CD40+ lymphoma cell lines showed and anti-tumour activity by CDX-1140, with attenuated tumour growth and increased survival, safety studies in cynomolgus macaques supported the use of the antibody in human [204,206,207]. A phase 1 trial (NCT03329950) is currently recruiting and will evaluate the safety and efficacy of CDX-1140 alone or in combination with the soluble recombinant Flt3 ligand, CDX-301, Pembrozilumab or chemotherapy (gemcitabine and nab-paclitaxel) [208].…”

Section: Cd40 Signalling and Inhibitionmentioning

confidence: 96%

“…CD40, a member of the TNF receptor family expressed by APCs (DCs, macrophages, NK cells, and mature B cells) interacts with its ligand, CD40L (CD154) expressed by activated T cells, stimulating cytokine secretion by B cells and allowing to T cell activation [202,203]. CD40 activation promotes the conversion of DCs to APCs, the phagocytic ability of macrophages, and the proliferation and antigen presentation on B cells [204]. CD40 is expressed in a wide range of B-NHL, CLL and MM [205].…”

Section: Cd40 Signalling and Inhibitionmentioning

confidence: 99%

Immune-Checkpoint Inhibitors in B-Cell Lymphoma

Armengol

Santos

Fernández-Serrano

et al. 2020

Preprint

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Immunotherapy has been considered for years as a viable and attractive treatment option for patients with cancer. Among immunotherapy arsenal, the targeting of intratumoral immune cells by immune-checkpoint inhibitory agents has recently revolutionized the treatment of several subtypes of tumours. These approaches aimed at restoring an effective anti-tumour immunity, rapidly reached the market thanks to the simultaneous identification of inhibitory signals that dampen an effective antitumor response in a large variety of neoplastic cells, and the clinical development of monoclonal antibodies targeting checkpoint receptors. Leading therapies in solid tumours are mainly focused on the cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) and programmed-death 1 (PD-1) pathways. These approaches have found a promising testing ground in both Hodgkin lymphoma and non-Hodgkin lymphoma, mainly because in these diseases the malignant cells interact with the immune system and commonly provide signals that regulate immune function. Although several trials have already demonstrated evidence of therapeutic activity with some checkpoint inhibitors in lymphoma, many of the immunologic lessons learned from solid tumours may not directly translate to lymphoid malignancies. In this sense, the mechanisms of effective antitumor responses are different between the different lymphoma subtypes, while the reasons for this substantial difference remain partially unknown. This review will discuss the current advances of immune-checkpoint blockade therapies in B-cell lymphoma and will build a projection of how the field may evolve in the near future. In particular, we will analyze the current strategies being evaluated both preclinically and clinically with the aim to foster the use of immune-checkpoint inhibitors in non-Hodgkin lymphoma, including combination approaches with chemotherapeutics, biological agents and/or different immunologic therapies.

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“…CD40, a member of the TNF receptor family expressed by APCs (DCs, macrophages, NK cells, and mature B-cells), interacts with its ligand CD40L (CD154), which is expressed by activated T-cells, stimulating cytokine secretion by B-cells and allowing T-cell activation [ 201 , 202 ]. CD40 activation promotes the conversion of DCs to APCs, the phagocytic ability of macrophages, and proliferation and antigen presentation on B-cells [ 203 ]. CD40 is expressed in a wide range of B-NHL, CLL and MM [ 204 ].…”

Section: Immune Checkpoint Blockade In B-cell Lymphomamentioning

confidence: 99%

“…Preclinical data showed enhanced DC and B-cell activation by CDX-1140, which synergises with recombinant CD40L to enhance agonist activity [ 205 ]. While xenograft models using CD40+ lymphoma cell lines have shown antitumour activity by CDX-1140, with attenuated tumour growth and increased survival, safety studies in cynomolgus macaques support the use of the antibody in humans [ 203 , 205 , 206 ]. A phase-1 trial (NCT03329950) is currently recruiting and will evaluate the safety and efficacy of CDX-1140 alone or in combination with the soluble recombinant Flt3 ligand CDX-301, pembrozilumab or chemotherapy (gemcitabine and nab-paclitaxel) [ 207 ].…”

Section: Immune Checkpoint Blockade In B-cell Lymphomamentioning

confidence: 99%

Immune-Checkpoint Inhibitors in B-Cell Lymphoma

Armengol

Santos

Fernández-Serrano

et al. 2021

Cancers

View full text Add to dashboard Cite

For years, immunotherapy has been considered a viable and attractive treatment option for patients with cancer. Among the immunotherapy arsenal, the targeting of intratumoral immune cells by immune-checkpoint inhibitory agents has recently revolutionised the treatment of several subtypes of tumours. These approaches, aimed at restoring an effective antitumour immunity, rapidly reached the market thanks to the simultaneous identification of inhibitory signals that dampen an effective antitumor response in a large variety of neoplastic cells and the clinical development of monoclonal antibodies targeting checkpoint receptors. Leading therapies in solid tumours are mainly focused on the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed death 1 (PD-1) pathways. These approaches have found a promising testing ground in both Hodgkin lymphoma and non-Hodgkin lymphoma, mainly because, in these diseases, the malignant cells interact with the immune system and commonly provide signals that regulate immune function. Although several trials have already demonstrated evidence of therapeutic activity with some checkpoint inhibitors in lymphoma, many of the immunologic lessons learned from solid tumours may not directly translate to lymphoid malignancies. In this sense, the mechanisms of effective antitumor responses are different between the different lymphoma subtypes, while the reasons for this substantial difference remain partially unknown. This review will discuss the current advances of immune-checkpoint blockade therapies in B-cell lymphoma and build a projection of how the field may evolve in the near future. In particular, we will analyse the current strategies being evaluated both preclinically and clinically, with the aim of fostering the use of immune-checkpoint inhibitors in lymphoma, including combination approaches with chemotherapeutics, biological agents and/or different immunologic therapies.

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CDX-1140, a Novel Agonist CD40 Antibody with Potent Anti-Lymphoma Activity

Cited by 7 publications

References 0 publications

Anti-CD40 Antibodies Fused to CD40 Ligand Have Superagonist Properties

Anti-CD40 Antibodies Fused to CD40 Ligand Have Superagonist Properties

Immune-Checkpoint Inhibitors in B-Cell Lymphoma

Immune-Checkpoint Inhibitors in B-Cell Lymphoma

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