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Induction of Antigen-Specific Immune Response with Use of Anti-Idiotypic Monoclonal Antibodies to Anti-Carcinoembryonic Antigen Antibodies1

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Induction of Antigen-Specific Immune Response with Use of Anti-Idiotypic Monoclonal Antibodies to Anti-Carcinoembryonic Antigen Antibodies1 (CANCER RESEARCH 51, 2599-2604, May 15, 1991] Induction of Antigen-specific Immune Response with Use of Anti-Idiotypic Monoclonal Antibodies to Anti-Carcinoembryonic Antigen Antibodies1 Masayuki Tsujisaki, Kohzoh linai, Shigeru Tokuchi, Yoshiaki Hanzawa, Tadao Ishida, Hiroshi Kitagawa, Yuji Hinoda, and Akira Yachi2 Department of Internal Medicine (Section 1), Sapporo Medical College, S-l, W-16, Chuo-ku. Sapporo, 060 [M. T., K. I., S. T., T. I., Y. H., A. Y.], Life Sciences Laboratories, Ajinomolo Co., Yokohama {Y. H.], Department of Basic Research, Hoechst Japan Limited, Kawagoe, Saitama [H. K.], Japan ABSTRACT Id MoAb (Ab2) to MoAb (Abl) reacting with tumor-specific transplantation antigen of rat sarcomas. When the Ab2 were Anti-idiotypic monoclonal antibodies (MoAbs) were prepared in a given to rats, they protected against challenge with the tumor. syngeneic system against anti-carcinoembryonic antigen (CEA) MoAb Kennedy et al. (8) reported that a combination of sera, which 5B3 (IgGl), which reacted with a carbohydrate moiety on CEA, and contained Ab2 relating to the amino-terminal and the carboxy- MoAb MA208 (IgGl), which reacted with a peptide on CEA. Anti- idiotypic MoAb T3-503 and T4-202 recognized the private idiotype of terminal peptides of the SV40 T-antigen, induced resistance in MoAb 5B3; anti-idiotypic MoAb M7-049 and M7-625 did so for MoAb mice to challenge with syngeneic SV40-induced tumor cells. As MA208. Idiotype mapping showed that MoAb 5B3 has at least two expected from studies on animal tumors, Ab2 could have been distinct idiotopes at its combining site and MoAb MA208 also has two. generated, relating to human cancer cells. Nepon et al. (9), for Four different anti-idiotypic MoAbs (Ab2) could induce anti-anti-idi- the first time, prepared polyclonal Ab2 by immunizing rabbits otypic antibodies (Ab3) specific to their respective immunizing anti- against a mouse anti-A/r 97,000 MAA MoAb 8.2. Recently, idiotypic MoAbs. Anti-anti-idiotypic MoAb M7-625 antiserum (at least Kahn et al. (10) demonstrated that some of monoclonal Ab2 a part of the antibodies) have the same reactivity as MoAb MA208, induced an Abl-like Ab3 response when given to either synge since the serum competed with the binding of MoAb MA208 against neic or allogeneic mice. CEA and contained the antibody population reactive with purified CEA in immunoblotting assay. These results suggest that anti-idiotypic MoAb We have carried out idiotype analysis by using anti-Id anti M7-625 bears the internal image of the antigen (CEA) and induces the bodies to anti-human high-molecular-weight MAA MoAbs (11, anti-anti-idiotypic antibodies specific to CEA. Therefore, an anti-idiotypic 12) in a syngeneic system. The results suggest that: (a) anti- antibody bearing the internal image of a tumor associated antigen might MAA MoAbs (Abl) were able to induce polyclonal anti-Id be used as a possible tool for vaccination or immunotherapy against antibodies (Ab2) specific to corresponding anti-MAA MoAb in malignant tumors as an antigen specific immunomodulator. a syngeneic mouse system; (b) polyclonal anti-Id antibodies inhibited the binding of anti-MAA MoAb to MAA on cultured melanoma cells, suggesting that the polyclonal anti-Id antibod INTRODUCTION ies included a population of anti-Id antibodies reactive with a The idiotype network theory proposed by Jerne (1) has been combining site of anti-MAA MoAb; (c) idiotype mapping uti accepted as a basic concept of immune regulation. This hypoth lizing anti-Id MoAbs showed that there might be several distinct esis of immune regulation proposes that idiotype-anti-idiotype idiotopes at combining and noncombining sites; (d) these anti- reactions control the response of a host to an antigen according Id MoAbs (Ab2) could also induce their anti-anti-Id antibodies to either an enhancing or suppressing feedback mechanism. (Ab3) specific to the corresponding immunizing anti-Id MoAb Numerous studies (2, 3) have acknowledged that idiotype net (Ab2) when the Ab2 was immunized in syngeneic BALB/c works have important roles in regulation of the immune mice. response. In the system of these human melanoma-associated antigens, In addition, Id3 antibodies have made it possible to analyze it has been very difficult to conclude clearly that anti-Id MoAb the genesis of autoimmune diseases and to perform structural carries the internal image of a given antigen, since the molecular analysis of receptors and ligands in receptor diseases (4). Re structure of MAA is not analyzed definitely. Recently, molec cently, Mendlovic et al. (5) reported that C3H mice developed ular cloning of CEA, one of the most useful tumor markers for the immunocomplex nephritis after injection with a human human colorectal carcinoma, was carried out and structural monoclonal anti-DNA antibody bearing Id-16/6. The animals analysis was developed. In order to investigate the internal developed not only high levels of anti-Id-16/6 but also anti- image from the molecular aspects and to determine what kind (anti-Id-16/6) antibodies that had anti-DNA activity. Also, anti- of anti-Id antibody is useful for vaccination or cancer therapy, Id antibody has successfully been applied as a vaccination to B- we have attempted to prepare a set of anti-Id MoAb relating to type viral hepatitis in animals (6). CEA. In experimental tumor system, Dunn et al. (1) generated anti- MATERIALS AND METHODS Received5/21/90;accepted3/7/91. The costs of publication of this article were defrayed in part by the payment Preparation of Purified CEA and NCA. Purified CEA and NCA of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. (nonspecific cross-reacting antigen) were prepared from colonie cancer 1Supported by grants for Cancer Research from the Ministry of Education, tissues and from normal lung tissues, respectively, by the immunoper- Science and Culture to A. Yachi and K. Imai, and from the Ministry of Health chloric extraction method followed by successive gel filtration as de and Welfare, Japan, to A. Y. This work was also supported and encouraged by scribed elsewhere (13). Purified CEA and NCA were used as antigens the Incitement Award of the Japanese Cancer Association to K. I. 2To whom requests for reprints should be addressed, at Department of Internal in the binding assay and in the immunoblotting assay. Medicine (Section 1), Sapporo Medical College, S-l, W-16. Chuo-ku, Sapporo Animals. Eight- to 12-week-old female BALB/c mice were purchased 060 Japan. 3The abbreviations used are: MoAbs, monoclonal antibodies; CEA, carcinoem- from Charles River Breeding Laboratories, Wilmington, MA. bryonic antigen; NCA, nonspecific cross-reacting antigen; Id, idiotypic; PBS, Development of Monoclonal Antibodies to CEA. The monoclonal phosphate-buffered saline; MAA, melanoma-associated antigen; PBS-T20, PBS antibodies were secreted by hybridomas constructed with myeloma cells containing 0.05% Tween 20. and splenocytes from BALB/c mice which were immunized with 3 2599 Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 1991 American Association for Cancer Research. ANTl-IDIOTVPIC MoAbs TO ANTI-CEA Abs weekly i.p. injections of 1 x IO7CEA-producing pancreatic carcinoma bound radioactivity was counted in a gamma counter. Results were cells Panel or 100 ^g of purified CEA. Hybridization with murine expressed as the percentage of binding inhibition as compared with myeloma cells P3x63-Ag 8.653, subcloning and growing of hybridomas control. were done according to standard procedures (13). Monoclonal antibod Idiotype Binding Assay. 125I-Labeled anti-idiotypic MoAb (1 x 10' ies 5B3 (IgGl) and MA208 (IgGl) had strong reactivity to purified cpm) were incubated for 3 h at 4°CwithMoAb-coated microtiter plates, CEA and CEA-producing cultured cells (MKN45, KATOIII, Panel, using the same procedure as in the sandwich assay. The plates were and WiDr), but neither reacted to purified NCA, meconium antigens, washed 5 times with PBS-T20, wells were cut, and the radioactivity nor CEA-nonproducing cells (K562 and Daudi) in binding assay. MoAb was counted in a gamma counter. 5B3 recognizes an epitope of carbohydrate moiety on CEA and MoAb Association constants (A,) of monoclonal antibodies were measured MA208 recognizes that of a peptide on CEA (14). according to Scatchard analysis (25). Briefly, 100 n\ of serial diluted Other Monoclonal Antibodies. The anti-CEA MoAbs, other than 5B3 '"¡-labeled anti-Id MoAbs (1.56 x 10~8~ 4.87 x IO'10 M) were added and MA208, were generous gifts from research groups of the Interna to the plates coated with MoAb MA208. Following 5 washings, bound tional Workshop (15). This Workshop on the epitope reactivity of cpm were counted. B/F and [B] were plotted to calculate A"aaccording MoAbs against CEA has summarized that anti-CEA MoAbs have been to the slope of the line [B, cpm of bound antibodies; F, cpm of free divided into 5 groups according to serological studies, mainly compe antibody; [B], concentration of bound antibody (M)]. tition assay. The studies indicate that anti-CEA MoAbs CEA 281 and Cross-blocking Assay. Microtiter plates were coated with MoAb 26/5/1; CEA 41 and 12-140-7; T84-66, II 10, and 12-140-1 were in (Abl) by incubating for 16 h at 4°C.After washing, an excess of cold the same groups, respectively ( 15). On the other hand, anti-CEA MoAbs anti-idiotypic MoAbs (Ab2) were added and incubated for 3 h at 4°C. YK024 and MT008 recognize the carbohydrate moiety on CEA (13). Following 3 washings, '"I-labeled anti-idiotypic MoAbs (1 x IO5cpm/ MoAb MA503 and MA504 recognize NCA which is a member of the well) were added to test for their ability to bind.
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