HSP65‐MUC1 is a fusion protein between BCG (Bacille Calmette‐Guerin)‐derived HSP65 (heat‐shock protein 65) and human MUC1 (mucin 1) VNTR (variable number of tandem repeats)‐domain peptides that has shown antitumour efficacy. China's Food and Drug Administration has recently approved a Phase I clinical trial using HSP65‐MUC1 for the treatment of MUC1‐positive breast cancer. In order to produce sufficient quantities of clinical‐grade HSP65‐MUC1, we established a pilot‐scale purification scheme comprising two steps of column chromatography: HIC (hydrophobic‐interaction chromatography) and IEX (ion‐exchange chromatography). The pH values of the buffers used in homogenization and HIC were adjusted to pH 9.0 to maintain protein stability and prevent protein degradation. Using this manufacturing process, we obtained clinical‐grade HSP65‐MUC1 with a yield of 400 mg per 70 g of wet cell pellet and >96% purity.

01 Nov 2008·Molecular ImmunologyQ3 · MEDICINE

Heat shock protein–antigen fusions lose their enhanced immunostimulatory capacity after endotoxin depletion

Q3 · MEDICINE

Article

Author: Boris Christian Marincek ; Marie Cristine Kühnle ; Frank Momburg ; Günter Hämmerling ; Cathy Srokowski ; Hansjörg Schild

Heat shock proteins (HSPs) induce cross-presentation of antigens by dendritic cells (DC) as well as DC maturation. These properties make HSP antigen complexes good candidates to prime CD8 T cell responses against tumor-associated antigens. In this study, we analyzed four different members of the HSP70 family fused to a fragment of ovalbumin (OVA) as a model tumor antigen. E. coli-derived recombinant HSP70-OVA fusion proteins efficiently primed antigen-specific cytotoxic T cells in short-term in vivo immunization assays. Because of concerns that the adjuvant effect of HSPs may be due to endotoxin contamination, we studied this issue in detail. Induction of OVA-specific cytotoxicity was significantly decreased in mice deficient for the LPS receptor, TLR4. After careful removal of endotoxins, immunization with HSP70-OVA failed to prime cytotoxic T cell responses. However, we obtained strong in vivo kill responses when endotoxin-depleted HSP70-OVA was used in combination with the TLR9 ligand CpG oligodeoxynucleotide 1668. Importantly, prophylactic and therapeutic treatment with endotoxin-depleted HSP70-OVA together with CpG significantly delayed the outgrowth of OVA-expressing B16 melanoma cells. However, we were unable to detect significant differences in the magnitudes of immune responses against endotoxin-depleted recombinant OVA vs. endotoxin-depleted HSP70-OVA fusion protein. Thus, immunization with recombinant HSP70-antigen fusion protein does not provide an advantage over recombinant antigen alone when combined with a suitable adjuvant. Altogether, our data suggest that the adjuvant effect of the HSP70 part of the fusion protein is completely lost after endotoxin removal.

15 Jan 1996·Journal of immunology (Baltimore, Md. : 1950)

Adjuvant-free hsp70 fusion protein system elicits humoral and cellular immune responses to HIV-1 p24.

Article

Author: Suzue, K ; Young, R A

Heat shock proteins are major targets of the immune response to bacterial and parasitic pathogens. Mycobacterium tuberculosis hsp70 is an especially powerful Ag containing multiple B and T cell epitopes. We investigated whether M. tuberculosis hsp70 can be used as an adjuvant-free carrier to stimulate the humoral and cellular immune response to an accompanying protein. A recombinant hsp70 protein expression vector was developed that permits the production of any protein fused to the amino terminus of mycobacterial hsp70. We found that a recombinant HIV p24-hsp70 fusion protein produced with this vector elicited both humoral and cellular immune responses against p24 in mice when administered in saline in the absence of adjuvant. Covalent linkage of hsp70 to p24 was essential to elicit immune responses to p24 under these conditions. The anti-p24 IgG1 Abs induced in p24-hsp70-immunized mice persisted at high levels for more than 1 yr after immunization. These results demonstrate that the antigenic properties of M. tuberculosis hsp70 can be exploited to enhance the humoral and cellular immune response to an attached protein.

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Indication	Highest Phase	Country/Location	Organization	Date
Breast Cancer	Phase 1	CN	Shanghai Xinshengyuan Biological Medicine Co. Ltd.	-

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