Vaccines prepared with sialyl-Tn and sialyl-Tn trimers using the 4-(4-maleimidomethyl)cyclohexane-1-carboxyl hydrazide linker group result in optimal antibody titers against ovine submaxillary mucin and sialyl-Tn-positive tumor cells Journal Article

  

Authors:	Ragupathi, G.; Howard, L.; Cappello, S.; Koganty, R. R.; Qiu, D.; Longenecker, B. M.; Reddish, M. A.; Lloyd, K. O.; Livingston, P. O.
Article Title:	Vaccines prepared with sialyl-Tn and sialyl-Tn trimers using the 4-(4-maleimidomethyl)cyclohexane-1-carboxyl hydrazide linker group result in optimal antibody titers against ovine submaxillary mucin and sialyl-Tn-positive tumor cells
Abstract:	Sialyl-Tn (STn) is an O-serine- or O-threonine-linked disaccharide [NeuAcα(2→6)GalN Acα-O-Ser/Thr) expressed on mucins of most types of adenocarcinoma as single STn or clustered STn [STn (c)] epitopes. Though STn is expressed on some normal tissues it is relatively tumor-specific, especially in the clustered conformation. Clinical trials with STn-keyhole limpet hemocyanin (KLH) conjugate vaccines, prepared using reductive amination with a two-carbon linker group, have resulted in high titers against STn but lower titers against natural forms of STn (ovine submaxillary mucin, or tumor cells). To obtain antibodies of more appropriate specificity, we attempted to prepare STn(c)KLH conjugates to establish their immunogenicity in mice in preparation for clinical trials; however, conjugation efficiency was poor when the same two-carbon linker was used, presumably because of steric hindrance. STn-KLH and STn(c)-KLH conjugates were prepared using the regular two-carbon or the recently developed more efficient longer heterobifunctional 4-(4-maleimidomethyl)cyclohexane-1- carboxyl hydrazide (MMCCH) linkers, and the resulting immunogenicities in mice were compared. The highest titers against STn were seen with the STn- KLH conjugate with the two-carbon linker, and the highest titers against STn(c) were seen with STn(c)-KLH with the MMCCH linker. Conjugation with MMCCH resulted in the highest conjugation efficiency (yield) and the highest titers against ovine submaxillary mucin and STn-positive tumor cells, and is the method of choice for the preparation of STn(c) vaccine for clinical trials.
Keywords:	nonhuman; adenocarcinoma; mouse; animals; mice; cancer immunotherapy; animal experiment; molecular sequence data; immunotherapy; immunoglobulin g; cancer vaccine; cancer vaccines; antibody response; cancer immunization; epitope; neoplasms, experimental; antibody specificity; enzyme-linked immunosorbent assay; amination; vaccine production; antibodies, neoplasm; vaccine; antigens, tumor-associated, carbohydrate; carbohydrate sequence; carbohydrate antigen; carbohydrate; antibody titer; sialic acid derivative; hemocyanin; immunoglobulin m; mucin; maleimides; mucins; conjugation; cross-linking reagents; immunoconjugates; drug conformation; sheep; cell sorter; submandibular gland; subcutaneous drug administration; female; priority journal; article; immunogen; sialyl tn
Journal Title:	Cancer Immunology, Immunotherapy
Volume:	48
Issue:	1
ISSN:	0340-7004
Publisher:	Springer
Date Published:	1999-04-01
Start Page:	1
End Page:	8
Language:	English
DOI:	10.1007/s002620050542
PUBMED:	10235483
PROVIDER:	scopus
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-0032892187&partnerID=40&md5=78b5a003c995df4afa0098997fa6fe43
Notes:	Article -- Export Date: 16 August 2016 -- Source: Scopus

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