Next-generation Anti-CD40 Agonist Antibody to Overcome Immunotherapy Resistance


Next-generation Anti-CD40 Agonist Antibody to Overcome Immunotherapy Resistance



Although immunotherapy with immune checkpoint blockade has had a major impact on cancer treatment, over 80% of cancer patients still do not benefit from it. A major reason for this is believed to be defective activation of antigen-presenting cells (APCs), particularly dendritic cells (DCs), which are responsible for priming T-cells. This defective APC activation may at least partially explain the absence of a productive anti-tumor T-cell response in immunotherapy-resistant cancers, including breast, colorectal, lung, and prostate cancer.

Stimulation of CD40 on APCs has been recognized as a highly effective way to activate APCs. MSK investigators have shown that a CD40 agonist antibody can effectively treat tumors as monotherapy and overcome resistance to PD-1 blockade in an immunocompetent mouse model that is resistant to immune checkpoint blockade. In addition, the investigators have described a novel way to use CD40 therapy to restore sensitivity to PD-1 blockade, confer persistent anti-tumor immunity, and overcome the challenge of T-cell exhaustion within tumors. In collaboration with the Tri-Institutional Therapeutics Discovery Institute, MSK researchers have developed a next-generation anti-CD40 agonist antibody designed to activate APCs without the requirement for Fc receptor engagement. The key features of the lead antibody (TDI-Y-003) are:

  • Nanomolar affinity for recombinant human CD40 in solution and binding to CD40-expressing cell lines
  • Competes with CD40L binding to prevent uncontrolled endogenous stimulation of CD40
  • Fc-receptor independence eliminates the necessity of sufficient myeloid infiltrate in the tumor microenvironment.
  • Demonstrates potent single agent anti-tumor activity in a humanized immunocompetent mouse model
  • Possesses favorable production and manufacturability properties


  • Fc-receptor independent activity and blocking CD40L binding reduces variability in response across patients and is differentiated from CD40 antibodies in clinical development
  • Superior activity in DC activation assay compared to other clinical CD40 antibodies
  • Potential to use as monotherapy or to combine with other immune-modulating agents that synergize with CD40 activation


There is a large unmet need for novel immune-modulating agents to overcome resistance to immune checkpoint inhibitors in solid tumors, including breast, colorectal, lung, and prostate cancer. CD40 therapy also may act as an adjuvant to stimulate the immune response against cancer vaccines and infectious disease vaccines.


  • PCT application PCT/US2021/063870 filed December 16, 2021.


  • Jedd Wolchok, MD, PhD, FASCO, former Laboratory Head and Chief, Immuno-Oncology Service, Memorial Hospital Research, Human Oncology & Pathogenesis Program, MSK


  • Danny N. Khalil et. al (2019) In situ vaccination with defined factors overcomes T-cell exhaustion in distant tumors, J Clin Invest. 129(8): 3435-3447 (PubMed link)


Lisa Kennedy, PhD

Associate Director, Technology Development

E-mail: [email protected]

Stage of Development

In vitro