Activity and safety of CTLA-4 blockade combined with vaccines in cynomolgus macaques
- PMID: 14634142
- DOI: 10.4049/jimmunol.171.11.6251
Activity and safety of CTLA-4 blockade combined with vaccines in cynomolgus macaques
Abstract
The immune modulatory molecule CTLA-4 (CD152), through interactions with the B7 costimulatory molecules, has been shown to be a negative regulator of T cell activation in various murine model systems. Abs that block CTLA-4 function can enhance immune responses that mediate potent antitumor activity. However, CTLA-4 blockade can also exacerbate autoimmune disease. The safety and activity of anti-CTLA-4 Abs in primates has not been addressed. To that end, we generated human Abs against CTLA-4 using transgenic mice expressing human Ig genes. A high affinity Ab (10D1) that blocked the binding of CTLA-4 to the B7-1 and B7-2 ligands and had cross-reactivity with macaque CTLA-4 was chosen for further development. Administration of 10D1 to cynomolgus macaques significantly enhanced Ab responses to hepatitis surface Ag and a human melanoma cell vaccine. Anti-self Ab responses as measured by immunoassays using lysate from melanocyte-rich tissues were elicited in those animals receiving the melanoma cell vaccine and anti-CTLA-4 Ab. Remarkably, chronic administration of 10D1 did not result in measurable polyclonal T cell activation, significant alteration of the lymphocyte subsets, or induce clinically observable autoimmunity. Repeated dosing of the 10D1 did not elicit monkey anti-human Ab responses in the monkeys. These observations support the development of CTLA-4 blockade for human immunotherapy.
Similar articles
-
Blockade of T cell activation using a surface-linked single-chain antibody to CTLA-4 (CD152).J Immunol. 2000 May 1;164(9):4433-42. doi: 10.4049/jimmunol.164.9.4433. J Immunol. 2000. PMID: 10779742
-
CTLA-4 gene polymorphism at position 49 in exon 1 reduces the inhibitory function of CTLA-4 and contributes to the pathogenesis of Graves' disease.J Immunol. 2000 Dec 1;165(11):6606-11. doi: 10.4049/jimmunol.165.11.6606. J Immunol. 2000. PMID: 11086105
-
Induction of CTL responses by simultaneous administration of liposomal peptide vaccine with anti-CD40 and anti-CTLA-4 mAb.J Immunol. 2000 Feb 1;164(3):1230-5. doi: 10.4049/jimmunol.164.3.1230. J Immunol. 2000. PMID: 10640735
-
[The immunotherapy potential of agonistic anti-CD137 (4-1BB) monoclonal antibodies for malignancies and chronic viral diseases].An Sist Sanit Navar. 2006 Jan-Apr;29(1):77-96. doi: 10.4321/s1137-66272006000100007. An Sist Sanit Navar. 2006. PMID: 16670731 Review. Spanish.
-
Complexities of CD28/B7: CTLA-4 costimulatory pathways in autoimmunity and transplantation.Annu Rev Immunol. 2001;19:225-52. doi: 10.1146/annurev.immunol.19.1.225. Annu Rev Immunol. 2001. PMID: 11244036 Review.
Cited by
-
The engagement of CTLA-4 on primary melanoma cell lines induces antibody-dependent cellular cytotoxicity and TNF-α production.J Transl Med. 2013 May 1;11:108. doi: 10.1186/1479-5876-11-108. J Transl Med. 2013. PMID: 23634660 Free PMC article.
-
Anti-CTLA4 Antibody Clinical Trials in Melanoma.Update Cancer Ther. 2007 Sep;2(3):133-139. doi: 10.1016/j.uct.2007.09.001. Update Cancer Ther. 2007. PMID: 19543441 Free PMC article.
-
T-cell modulation combined with intratumoral CpG cures lymphoma in a mouse model without the need for chemotherapy.Blood. 2009 Apr 9;113(15):3546-52. doi: 10.1182/blood-2008-07-170274. Epub 2008 Oct 21. Blood. 2009. PMID: 18941113 Free PMC article.
-
Ipilimumab: from preclinical development to future clinical perspectives in melanoma.Future Oncol. 2017 Mar;13(7):625-636. doi: 10.2217/fon-2016-0385. Epub 2016 Nov 24. Future Oncol. 2017. PMID: 27882779 Free PMC article. Review.
-
T-cell exhaustion in chronic hepatitis B infection: current knowledge and clinical significance.Cell Death Dis. 2015 Mar 19;6(3):e1694. doi: 10.1038/cddis.2015.42. Cell Death Dis. 2015. PMID: 25789969 Free PMC article. Review.
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
