Bioconjugates of nanoparticles as radiopharmaceuticals

Details Bioconjugates of nanoparticles as radiopharmaceuticals Bioconjugates of nanoparticles as radiopharmaceuticals

2001-05-31

2004-02-10

Padmanabhan, Sreeni (Department: 1619)

Drug, bio-affecting and body treating compositions

Radionuclide or intended radionuclide containing; adjuvant...

In an organic compound

C424S618000, C424S637000, C424S646000, C424S654000, C424S706000

Reexamination Certificate

active

06689338

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates generally to the effective diagnosis and treatment of cancer patients and, more specifically, to radiopharmaceuticals for use in connection with radioimmunotherapy and radioimmunodection.
2. Background
Effective treatment of cancer patients by using radioimmunotherapy (RAIT) and diagnostics of malignant tumors by radioimmunodetection (RAID) requires drastic improvement of tumor-to-background (T/B) distribution of a radiolabel. T/B ratio is the principal parameter that determines tumoricidal action, sensitivity of tumor detection and, most importantly, systemic toxicity of the compound. Radioactive isotopes of metals are used very often in various modalities of RAIT and RAID in the form of conjugates with monoclonal antibodies (mAbs).
Attachment of the radioisotope to the targeting molecule is the most important part of the preparation of the radioconjugate. In some cases, a direct approach to radiolabeling of antibodies with therapeutic radionuclides can be adopted by reducing internal disulfide bonds within the antibody and allowing, for example, technetium or rhenium ions to react directly with the resultant sulfhydryl groups. However, labeling strategies usually rely on the utilization of a multidentate ligand capable of selective chelation of the desired radionuclide. In order to avoid the release of the metal ion in the circulation and inevitable radiation injuries to healthy organs, metal ions must be strongly complexed by a chelating agent.
Ideally, the chelated nuclide would be rapidly excreted via the urinary tract without intracellular retention, with intact conjugate accumulating and being retained selectively at the tumor site. This is however clearly not always the case, and in several instances, persistent and unwanted retention of metallic nuclides has been reported. As the in vivo behavior of a given nuclide-chelator complex cannot be predicted easily, the choice of potential multidentate ligands is guided by conventional chelation chemistry. Macrocyclic multidentate ligands which provide the highest thermodynamic stability of the complex are frequently used for preparation of immunoconjugates. The typical examples of chelating agents are diethylenetriaminepentaacetic anhydride (DTPA), (diethylenetriaminetetraacetic acid (DTTA), (1,4,7,10-tetraazacyclododecane-N,N═,N
,N
═-tetraacetic acid) (DOTA), ethylenediaminetetra(methylene phosphonate) (EDTMP), 1,1-hydroxyethylidine diphosphonate(HEDP) and derivatives thereof. For preparation of conjugated structures they are frequently functionalized in one of the side chains by —C
6
H
4
—NCS or other groups to form a covalent bond with proteins.
Entrapment of metal ion into a framework of muldidentate poly (amino carboxylates) such as DOTA, DTPA covalently attached to mAbs has been proven to provide thermodynamically stable compounds suitable for clinical trials. Nevertheless, results obtained for human patients and for animal models indicate that the applicability of these compounds is limited by the high level of radioactivity in blood, bone marrow, kidney and liver. This necessitates reduction of in-vivo decomplexation of metal ions and strengthening radiolabel-mAb bond.
The tumor uptake and overall biodistribution of the radiolabeled compound depends on the metabolism of the mAb and the strength of radionuclide-antibody link. Although there is a substantial room for improving targeting properties of mAbs, all studies indicate that the thermodynamic and kinetic stability of the chelate in vivo of is of primary importance for the design of clinically successful radiochemicals.
The equilibrium constant of chelation for the best chelates used in RAIT and RAID is comparable to that for some proteins present in blood. Therefore, chelates are inherently prone to slow exchange of radioactivity with tumor-indifferent proteins. When radiopharmaceuticals are administered intravenously, they encounter endogenous metal-binding proteins such as albumin in concentrations 100-1000-fold greater than that of the radiopharmaceutical. Loss of radiometal to serum proteins leads to accumulation of radioactivity in normal tissues, especially liver, spleen, and kidney, reducing the radioactivity available for tumor uptake. Stability of the radioimmunoconjugate is a critically important factor in determining its usefulness for in vivo applications. This fact was experimentally established for the majority of radionuclides.
For complexes of
111
In and bleomycin, partial dissociation of the ion from bleomycin caused severe bone marrow toxicity and increased the background &ggr;-radiation significantly impairing its therapeutic and imaging capabilities. The tumor-to-background ratio varied from 1.0 to 2.9. Even for one of the most widely used and the strongest
111
In chelate with octadentate ligand DTPA (K
diss
=28.5) a high liver background has been observed. Most researchers agree that chelate instability is the primary reason for various immune mechanisms which contribute to accumulation of the radioactivity in non target organs. Recent study clearly indicate the direct dependence between the thermodynamic stability of various chelates (NTA, EGTA, EDTA, DTPA) bound to the B72.3 antibody and the tissue distribution and accumulated activity in blood and kidney.
Retention of
111
In in normal tissues has been the major limitation in RAID applications. Improved clearance of
111
In from liver tissue correlated with the strength of a labile linkage between the antibody and the chelator and with the structure of the chelator to provide for higher stability under in vivo conditions.
The loss of metal ion in circulation greatly limits the utilization of potent radionuclides with convenient energy and half-life characteristics such as
212
Pb. The short decay of
212
Pb time (10.6 hours, &bgr;, 0.57 and 0.33 MeV) permits rapid clearance from the system. When conjugated to specific mAb 103 A,
212
Pb-DOTA chelate was very efficacious at eliminating the tumor even in mice with large tumor burdens. However, due to lower pH values found in cells in which catabolism occurs,
212
Pb escapes the chelator and is taken up in bone and marrow. Bone marrow toxicity in this case was so high that accumulation of
212
Pb in bones was dose limiting and lethal. Loss of the specificity of radiometal deposition was observed for
46
Sc,
67
Ga, and
90
Y when the ion was not strongly chelated to its ligand.
Incorporation of a radiometal label into the protein structure by using nitrogen and sulfur atoms of aminoacids (NS systems) is very popular for technetium and rhenium. Comparative stability of these chelates is quite high. Importantly, metal species can be incorporated in an anionic form that makes recomplexation by native proteins less probable. Nevertheless,
188
Re-labeled mAbs were found to be a marginal agent for controlling tumor growth. The failure of
188
Re-IgG in some tumor models may be related to the combination of apparent instability of the labeled product and its short physical half-life. Interestingly the dissociation of
188
Re from the protein occurred more quickly that for other isotopes such as
88
Y. The release of rhenium is likely to be assisted by reoxydation of the chelate to ReO
4
−
by dissolved oxygen.
Importantly, for yttrium (
90
Y,
88
Y), lead (
212
Pb) and samarium (
153
Sm) the strength of the chelates must be particularly high. In ionic form these metals are capable of replacing Ca
2+
ions from bone, which halts excretion of the radionuclide and causes augmented radiation damage to healthy tissues.
The nature of medical applications imposes multiple requirements on the chemical characteristics of a potential chelating ligand. It has to be (a) strong (multidentate) complexing agent for the metal ion, (b) hydrophilic to afford solubility in water, (c) nontoxic, (d) capable of incorporating into a protein structure without causing its denaturation. For virtually every single radionuclide one has to design a special chelating sy

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