Engineering a Therapeutic Protein to Enhance the Study of Anti-Drug Immunity

被引:1
作者
Zerra, Patricia E. [1 ,2 ]
Parker, Ernest T. [2 ]
Baldwin, Wallace Hunter [2 ]
Healey, John F. [2 ]
Patel, Seema R. [2 ]
McCoy, James W. [1 ]
Cox, Courtney [2 ]
Stowell, Sean R. [3 ]
Meeks, Shannon L. [2 ]
机构
[1] Emory Univ, Ctr Transfus Med & Cellular Therapies, Dept Lab Med & Pathol, Atlanta, GA 30322 USA
[2] Emory Univ, Aflac Canc & Blood Disorders Ctr, Childrens Healthcare Atlanta, Dept Pediat, Atlanta, GA 30322 USA
[3] Harvard Med Sch, Dept Pathol, Joint Program Transfus Med, Boston, MA 02115 USA
基金
美国国家卫生研究院;
关键词
anti-drug antibodies; hemophilia A; factor VIII inhibitors; humoral immunity; FACTOR-VIII INHIBITORS; RECOMBINANT FACTOR-VIII; HEMOPHILIA-A PATIENT; T-CELLS; REPLACEMENT THERAPY; MAJOR DETERMINANT; TRANSGENIC MICE; B-CELLS; MODEL; IMMUNOGENICITY;
D O I
10.3390/biomedicines10071724
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The development of anti-drug antibodies represents a significant barrier to the utilization of protein-based therapies for a wide variety of diseases. While the rate of antibody formation can vary depending on the therapeutic employed and the target patient population receiving the drug, the antigen-specific immune response underlying the development of anti-drug antibodies often remains difficult to define. This is especially true for patients with hemophilia A who, following exposure, develop antibodies against the coagulation factor, factor VIII (FVIII). Models capable of studying this response in an antigen-specific manner have been lacking. To overcome this challenge, we engineered FVIII to contain a peptide (323-339) from the model antigen ovalbumin (OVA), a very common tool used to study antigen-specific immunity. FVIII with an OVA peptide (FVIII-OVA) retained clotting activity and possessed the ability to activate CD4 T cells specific to OVA(323-339) in vitro. When compared to FVIII alone, FVIII-OVA also exhibited a similar level of immunogenicity, suggesting that the presence of OVA(323-339) does not substantially alter the anti-FVIII immune response. Intriguingly, while little CD4 T cell response could be observed following exposure to FVIII-OVA alone, inclusion of anti-FVIII antibodies, recently shown to favorably modulate anti-FVIII immune responses, significantly enhanced CD4 T cell activation following FVIII-OVA exposure. These results demonstrate that model antigens can be incorporated into a therapeutic protein to study antigen-specific responses and more specifically that the CD4 T cell response to FVIII-OVA can be augmented by pre-existing anti-FVIII antibodies.
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页数:17
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