Processes and products with modified antibodies of human milk fat globule specificity

Abstract

An analogue peptide that comprises the variable regions of the light or heavy chains of an antibody of a first species selectively binding to a carcinoma antigen has 1 to 46 amino acids of the framework regions per chain substituted with amino acids such as those present in equivalent positions in antibodies of a species other than the first species, or fragments thereof comprising 1 to 3 variable region CDRs per chain and optionally flanking regions thereof of 1 to 10 or more amino acids, alone or with an N-terminal fragment of 1 to 10 or more amino acids, combinations or mixtures thereof. The polypeptide may also comprise an effector agent and / or be glycosylated, and is presented as a composition with a carrier. The analogue peptides are used in diagnostic kits for carcinomas and methods for in vivo imaging and treating a primary or metastasized carcinoma, and in vitro diagnosing a carcinoma, ex vivo purging neoplastic cells from a biological fluid. RNAs and DNAs encode the analogue peptide, and a hybrid vector carrying the nucleotides and transfected cells express the peptides and a method produces the analogue peptide. An anti-idiotype polypeptide comprises polyclonal antibodies raised against an anti-carcinoma antibody or the analogue peptide of this invention, monoclonal antibodies thereof, Fab, Fab′, (Fab′)2, CDR, variable region, or analogues or fragments thereof, combinations thereof with an oligopeptide comprising a TRP trimer, tandem repeats thereof, or combination or mixtures thereof. An anti-idiotype hybrid polypeptide with an effector agent and the anti-idiotype polypeptide, an anti-carcinoma vaccine, an anti-carcinoma vaccination kit, a method of vaccinating against carcinoma and a method of lowering the serum concentration of a circulating antibody or polypeptide are provided.

Description

[0001] This application is a divisional of U.S. Ser. No. 08 / 129,930, entitled “MODIFIED ANTIBODIES WITH HUMAN MILK FAT GLOBULE SPECIFICITY”, filed on Sep. 30, 1993, by the same inventors, now U.S. Pat. No. 5,804,187, which is a continuation-in-part of U.S. Ser. No. 07 / 977,696, entitled “POLYNUCLEOTIDES ENCODING MODIFIED ANTIBODIES WITH HUMAN MILK FAT GLOBULE SPECIFICITY”, filed Nov. 12, 1992, by Do Couto, Ceriani and Peterson, now U.S. Pat. No. 5,792,852.BACKGROUND OF THE INVENTION [0002] 1. Field of the Invention [0003] This invention relates to the in vitro and in vivo diagnosis, immunization, and therapy of neoplastic tumors, particularly carcinomas, by means of specifically targeted analogue peptides comprising amino acid sequences encompassing the complementarity determining regions (CDRs) of a different species, and analogues of the variable (Fv) region of anti-carcinoma antibodies, among others. The carcinoma specific peptides for use in one species, e.g., humans, are provide...

AI Technical Summary

Benefits of technology

The analogue peptides demonstrate reduced immunological response and maintain high affinity and specificity for carcinoma antigens, enabling effective and repeated use in humans with minimized side effects.

Problems solved by technology

Two of the most damaging characteristics of carcinomas are their uncontrolled growth and their ability to create metastases in distant sites of the host, particularly a human host.

It is usually these distant metastases that cause serious consequences to the host, since frequently the primary carcinoma may be, in most cases, removed by surgery.

Chemotherapy produces serious toxic effects on normal tissues, making the chemotherapy of carcinomas less than desirable, and the use of radiolabeled monoclonal antibodies a valid alternative.

Unfortunately, 2 to 3 weeks after treatment, the patients developed a strong human anti-murine antibody (HAMA) response that prevented further administration of the radioimmunoconjugate.

The anti-heterologous human response is, thus, a substantial limiting factor hindering the successful use of heterologous monoclonal antibodies as therapeutic agents, which could, otherwise, specifically annihilate breast carcinomas, causing little or no damage to normal tissue and having no other toxic effects.

However, the procedures employed to accomplish CDR-grafting often result in imperfectly “humanized” antibodies.

Hence, they should be poorly immunogenic, if at all, when presented to a recipient organism.