We previously conducted a clinical study to assess the therapeutic potential of recombinant human CD40 ligand in patients with XHM. We designed a one-center investigator-initiated Phase I/II clinical trial (protocol 00-I-0006) to assess safety of recombinant CD40L administration, and determine if it could restore the core immunologic defects of patients with XHM. Five patients were enrolled, and were treated on a dose escalation schedule for up to one year. We showed that administration of recombinant CD40 ligand is safe and can reconstitute deficient immune responses. Specifically, patients T cells demonstrate for the first time a capacity to synthesize IFN-γand TNF-αwhen stimulated with anti- CD3, or SEB, or SEA. Studies of cytokine production by intracellular staining demonstrated that recombinant CD40L was able to prime both the CD4 and CD8 T cell populations. In addition, all patients developed positive delayed type hypersensitivity reactions to candida, and KLH, and one patient to mumps antigen. Patients on therapy also demonstrated the development of new adenopathy, improvement of primary follicle formation, expansion of both B and T cell populations in the lymphnodes, and the development of follicular dendritic cells. However, germinal center formation and immunoglobulin class switch recombination (CSR) in B cells was lacking. Further improvements in B cell terminal differentiation may require higher doses or a different class of drugs that offer greater half-life. Stimulated by these observations, we have initiated a a single center dose escalation pilot study with a fully human CD40 agonist antibody in XHM patients. Preliminary results indicate the anti- CD40 agonist antibody has significant biological activity in vivo. Human CD40 agonist antibody therapy may allow for less frequent dosing and a reduced risk of serious toxicity in study patients.

Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2009
Total Cost
$411,530
Indirect Cost
City
State
Country
Zip Code
Fan, Xiying; Upadhyaya, Bhaskar; Wu, Liming et al. (2012) CD40 agonist antibody mediated improvement of chronic Cryptosporidium infection in patients with X-linked hyper IgM syndrome. Clin Immunol 143:152-61
Jain, Ashish; Kovacs, Joseph A; Nelson, David L et al. (2011) Partial immune reconstitution of X-linked hyper IgM syndrome with recombinant CD40 ligand. Blood 118:3811-7
Murray, Patrick R; Jain, Ashish; Uzel, Gulbu et al. (2010) Pyoderma gangrenosum-like ulcer in a patient with X-linked agammaglobulinemia: identification of Helicobacter bilis by mass spectrometry analysis. Arch Dermatol 146:523-6
Wang, Hong-Ying; Gopalan, Vivek; Aksentijevich, Ivona et al. (2010) A custom 148 gene-based resequencing chip and the SNP explorer software: new tools to study antibody deficiency. Hum Mutat 31:1080-8
Bishu, Shrinivas; Madhavan, Deepak; Perez, Phillip et al. (2009) CD40 ligand deficiency: neurologic sequelae with radiographic correlation. Pediatr Neurol 41:419-27
Salt, Bryn H; Niemela, Julie E; Pandey, Rahul et al. (2008) IKBKG (nuclear factor-kappa B essential modulator) mutation can be associated with opportunistic infection without impairing Toll-like receptor function. J Allergy Clin Immunol 121:976-82
Lopez-Granados, Eduardo; Keenan, Jeffrey E; Kinney, Matthew C et al. (2008) A novel mutation in NFKBIA/IKBA results in a degradation-resistant N-truncated protein and is associated with ectodermal dysplasia with immunodeficiency. Hum Mutat 29:861-8