Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Blood proteins or globulins – e.g. – proteoglycans – platelet...
Patent
1996-09-18
1998-09-15
Achutamurthy, Ponnathapura
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Blood proteins or globulins, e.g., proteoglycans, platelet...
436504, 436545, 436546, 5303911, 5303913, 530405, 530409, 540460, 558 17, 562434, 562437, 562450, 564196, 564367, 564368, 564369, C07K 1600, C07K 1700, A61K 5108, C07C33128
Patent
active
058080031
DESCRIPTION:
BRIEF SUMMARY
This invention relates to new chelating agents for attaching metal ions to peptides and proteins such as albumin, transferrin, antibodies and antibody fragments.
BACKGROUND OF THE INVENTION
Attachment of metal ions to proteins leads to several useful products. These include fluorescent, radioactive and paramagnetic metal ions attached proteins that can be used as probes in vivo in biological systems and in vitro in analytical systems, such as radioimmunoassays. For example, attachment of radionuclides to monoclonal antibodies that recognize tumor associated antigens provides radioimmunoconjugates useful for cancer diagnosis and therapy. The monoclonal antibodies are used as carriers of desired substances to specific sites in-vivo. Several chelating agents, such as diethylenetriaminepentaacetic acid (DTPA), ethylenediaminetetraacetic acid (EDTA) and macrocyclics, have been reported to form stable complexes when attached to proteins. However, kinetic instability of the radioimmunoconjugate or the chelate under physiological conditions results in the breakdown of these complexes. Despite several attempts to modify the mode of binding, structure of chelate and etc., in vivo administration of such radioimmunoconjugates has resulted in accumulation of radioactivity in non-target tissues, particularly in the liver. Hence, there is an obvious need for new chelating agents for binding radiometals to antibodies to form complexes that do not disassociate when administered to a patient.
It is an object of this invention to provide a new set of chelating agents for attaching metal ions to proteins and thereby provide an aqueous solution containing antibody-chelate conjugate that is stable in vivo.
It is further an object of this invention to provide a set of chelating agents to bind a variety of metal ions, including In, Y, Gd, Tb, Eu, Cu, Co, Sm, Rh, Ru, Re, Bi, Tl, Tc, Fe, Pb and Ba, Lu, as well other actinides, lanthanides and transition metal ions.
It is further an object of this invention to synthesize new chelation structures useful for attaching metal ions to proteins, including monoclonal antibodies.
It is another object of this invention to obtain versatile chelating agents that are not only suitable for binding to low molecular weight proteins, such as albumin and IgG, but also to high molecular weight proteins, such as IgMs (9.times.10.sup.5) and lipoproteins (2.times.10.sup.6).
It is still another object of this invention to obtain an improved method for preparing metal chelate conjugated antibodies.
An additional object of this invention is to obtain chelation structures that provide a high metal ion concentration per antibody molecule without destroying the biological activity of the conjugated protein to a significant extent.
It is still another object of this invention to obtain fluorescent labeled proteins by attaching fluorescent/luminescent metal ions to protein-chelate conjugates.
It is further the object of this invention to obtain metal ion binding reagents that can be attached to chromatographic column materials such as polymers and gels, forming chelate affinity columns.
These and other objects are accomplished by one or more of the embodiments of the present invention.
BRIEF DESCRIPTION OF DRAWINGS
FIG. 1 Polyamine structure.
FIG. 2 provides the structure of LiLo2'.
FIG. 3 provides the structure of HETA2.
FIG. 4 illustrates the synthetic route employed in the preparation of HETA2 and LiLo2'.
FIG. 5 illustrates the stability of Y(90) labeled 16.88-LiLo2' in human serum. In this figure, the incubation time (37.degree. C.) is plotted against the percentage of Y(90) bound to 16.88-LiLo.
Table 1 gives the percentage of indium(111) bound to 16.88-LiLo2' as a function of time of incubation in the presence of excess DTPA (indium-111.MoAb:DTPA=1:>5000) at 37.degree. C., as well as in phosphate buffered saline solution containing 1% HSA solution.
Table 2 represents the stability of 88BV59-HETA2.In(111) in several solutions: in the presence of excess of DTPA (indium-111.MoAb:DTPA=1:>5000) at 3
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Colony James
Subramanian Ramaswamy
Achutamurthy Ponnathapura
Blackstone William M.
PerImmune Holdings, Inc.
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