There are provided a compound of Formula (1) and a labeled biological substance having the compound.

##STR00001##

R.sup.1 to R.sup.6, R.sup.11 to R.sup.13, and R.sup.22 to R.sup.29 represent specific groups, and n is an integer of 1 to 3.

One selected from R.sup.1, R.sup.2, R.sup.5, R.sup.22 to R.sup.25 and one selected from R.sup.3, R.sup.4, R.sup.6, and R.sup.26 to R.sup.29 are bonded through a linking group LL.

The linking group LL represents a linking group having 1 to 100 atoms, which does not have any one of an aromatic hydrocarbon ring, a sulfo group, or a phosphono group.

R.sup.1, . . . , R.sup.6, R.sup.22, . . . , or R.sup.29 includes a structure represented by —(CH.sub.2—CH.sub.2—O).sub.m—, where m is 1 to 50.

The above-described compound is a neutral compound and contains at least one substituent capable of being bonded to a carboxy group or a biological substance.

Modular Meldrum's acid amine-reactive Michael acceptor (MaMa)—based molecules that are stable probes for high pH environents and bioconjugations. The molecules of the present invention can selectively label and protect lysine residues. In certain embodiments, the molecules can selectively react with lysine at particular pH levels. The probes of the present invention may be used to label proteins in a fluorescent manner, for purification, imaging, or general protein modifications, however the present invention is not limited to the aforementioned applications.

Modular Meldrum's acid amine-reactive Michael acceptor (MaMa)—based molecules that are stable probes for high pH environents and bioconjugations. The molecules of the present invention can selectively label and protect lysine residues. In certain embodiments, the molecules can selectively react with lysine at particular pH levels. The probes of the present invention may be used to label proteins in a fluorescent manner, for purification, imaging, or general protein modifications, however the present invention is not limited to the aforementioned applications.

Antibodies that include a sulfatase motif-containing tag in a constant region of an immunoglobulin (Ig) heavy chain polypeptide are disclosed. The sulfatase motif can be converted by a formylglycine-generating enzyme (FGE) to produce a formylglycine (fGly)-modified Ig heavy chain polypeptide. An fGly-modified Ig heavy chain polypeptide of the antibody can be covalently and site-specifically bound to a moiety of interest to provide an antibody conjugate. The disclosure also encompasses methods of production of such tagged Ig heavy chain polypeptides, fGly-modified Ig heavy chain polypeptides, and antibody conjugates, as well as methods of use of same.

A gastrin analogue shows high uptake in CCK-2 receptor positive tumors and simultaneously a very low accumulation in the kidneys. This is achieved by a mini-gastrin analogue PP-F11 having the formula: PP-F11-X-DGlu-DGlu-DGlu-DGlu-DGlu-DGlu-Ala-Tyr-Gly-Trp-Y-Asp-Phe-NH.sub.2, wherein Y is an amino acid replacing methionine and X is a chemical group attached to the peptide for diagnostic and/or therapeutic intervention at CCK-2 receptor relevant diseases. Very suitable compounds with respect to a high tumor to kidney ratio are mini-gastrin analogues with six D-glutamic acids or six glutamines. These compounds still possess a methionine which can be oxidized easily which is a disadvantage for clinical application under GMP due to the forms which may occur. The elimination of the methionine leads to a lower affinity to oxidation which in general favors the tumor-kidney-ratio. Ideally, the methionine is replaced by norleucine. This PP-F11N mini gastrin exhibits currently the best tumor-kidney-ratio and is the most promising candidate.

A gastrin analogue shows high uptake in CCK-2 receptor positive tumors and simultaneously a very low accumulation in the kidneys. This is achieved by a mini-gastrin analogue PP-F11 having the formula: PP-F11-X-DGlu-DGlu-DGlu-DGlu-DGlu-DGlu-Ala-Tyr-Gly-Trp-Y-Asp-Phe-NH.sub.2, wherein Y is an amino acid replacing methionine and X is a chemical group attached to the peptide for diagnostic and/or therapeutic intervention at CCK-2 receptor relevant diseases. Very suitable compounds with respect to a high tumor to kidney ratio are mini-gastrin analogues with six D-glutamic acids or six glutamines. These compounds still possess a methionine which can be oxidized easily which is a disadvantage for clinical application under GMP due to the forms which may occur. The elimination of the methionine leads to a lower affinity to oxidation which in general favors the tumor-kidney-ratio. Ideally, the methionine is replaced by norleucine. This PP-F11N mini gastrin exhibits currently the best tumor-kidney-ratio and is the most promising candidate.

The present invention relates to methods to use cyclohexan-1,2-dione (CHD) groups to attach labels, linkers, and other molecules to a target compound comprising a CHD-reactive group such as a guanidine, amidine, urea, thiourea and the like. Methods of the invention include milder conditions than those previously known for promoting reaction of CHD with CHD-reactive groups, which makes the methods suitable for use with base-sensitive compounds and complex biomolecules. Methods of the invention are especially useful for attaching linking and labeling groups to a peptide that comprises at least one arginine residue, and can also be used to link such peptides to other target molecules such as nucleic acids. The invention also provides CHD-containing conjugation reagents and compositions comprising CHD-containing intermediates, and precursors useful for making CHD-containing compounds that can be used in the methods of the invention.

The present invention relates to methods to use cyclohexan-1,2-dione (CHD) groups to attach labels, linkers, and other molecules to a target compound comprising a CHD-reactive group such as a guanidine, amidine, urea, thiourea and the like. Methods of the invention include milder conditions than those previously known for promoting reaction of CHD with CHD-reactive groups, which makes the methods suitable for use with base-sensitive compounds and complex biomolecules. Methods of the invention are especially useful for attaching linking and labeling groups to a peptide that comprises at least one arginine residue, and can also be used to link such peptides to other target molecules such as nucleic acids. The invention also provides CHD-containing conjugation reagents and compositions comprising CHD-containing intermediates, and precursors useful for making CHD-containing compounds that can be used in the methods of the invention.

This invention provides compositions comprising linked amino acid sequences, pharmaceutical compositions comprising linked amino acid sequences, and methods of making thereof. This invention also provides methods of delivering said compositions to subjects and methods of treating various disorders and diseases using the said compositions.

The present invention provides new polypeptide derivatives binding to Human Epidermal Growth Factor Receptor 2 (HER2) and their conjugates thereof, and to their use as a diagnostic agent, particularly for early detection, patient stratification and treatment monitoring of forms of cancer characterized by over-expression of HER2.