Actinium-225 complexes and conjugates for targeted radiotherapy

Details Actinium-225 complexes and conjugates for targeted radiotherapy Actinium-225 complexes and conjugates for targeted radiotherapy

2002-02-27

2003-12-30

Jones, Dameron L. (Department: 1616)

Organic compounds -- part of the class 532-570 series

Organic compounds

Radioactive metal containing

C424S001110, C424S001650, C424S009100, C514S156000, C514S183000, C514S188000, C514S241000, C514S247000

Reexamination Certificate

active

06670456

ABSTRACT:

This invention relates to actinium-225 (
225
Ac) complexes with fuctionalized chelants, their conjugates and their use for targeted radiotherapy.
The use of radionuclides complexed with suitable chelants, as well as their conjugates (that is, such complexes covalently attached to a biologically active carrier, e.g., protein) for diagnosis of cancer and/or therapeutic treatment of cancer in mammals is known. These biochemically engineered molecules provide the tumor specificity and the radioisotope provides potent cytotoxicity. See, for example, U.S. Pat. Nos. 4,897,254; 5,342,925; 5,435,990; 5,652,361; 5,696,239; and 5,756,065.
It has been recognized that antibody-targeted alpha particles would allow extraordinarily potent, single cell-specific killing with minimal toxicity to normal cells or the patient. The use of alpha particles as an alternative to more traditional classes of radiation is derived from the particle's kinetic characteristics and the radioactive half-life of their source isotope, as well as from the properties of the target-selective carrier moiety for the source isotope. The use of alpha-emitting radionuclides is highly desirable for the following reasons: (a) a single atom can kill a cell making them hundreds to thousands of times more potent than even the most potent toxins or drugs; (b) the range of alpha particles is only about 50 microns, so that adjacent tissues are not harmed; (c) the chelated atoms on fully human or humanized antibodies are unlikely to be immunogenic and can be repeatedly dosed; (d) the radioactive atoms decay to harmless stable atoms; (e) killing can occur from inside or outside of the cell; (f) killing is by apoptosis and by double stranded DNA breaks and repair is not likely.
Specific cytotoxic effects of “alpha particle-emitting radioimmunoconjugates” have been demonstrated in several experimental systems. Specific in vitro cell-killing has been demonstrated against a human epidermoid cell line using
213
Bi- and
225
Ac-containing immunoconjugates, see, for example, Kaspersen et al, Nuclear Medicine Communications, Vol. 15, pp. 468-476 (1995). Efficient and specific cell kill by the
212
Bi-labeled anti-Tac (CD25) monoclonal antibody has been demonstrated against an adult T-cell leukemia cell line in vitro, see, for example, R. W. Kozak et al, Proc. Natl. Acad. Sci. USA, Vol. 83, pp. 474-478 (1986). In other experiments, mice inoculated intraperitoneally with the murine tumor line EL-4 were cured of their ascites after intraperitoneal injection of 150 &mgr;Ci of a
212
Bi-labeled antibody conjugate, see, for example, R. M. Macklis et al, Science, Vol. 240, pp. 1024-1026 (1988).
Potential for use of
225
Ac in radiotherapy of cancer has also been recognized due to its favorable properties. This isotope decays with a radioactive half-life of 10 days into a cascade of short lived alpha- and beta-emitting isotopes. See, for example, M. W. Geerlings et al, Nuclear Medicine Communications, Vol. 14, pp. 121-125 (1993) and Kaspersen et al, Nuclear Medicine Communications, Vol. 15, pp. 468-476 (1995). However, the use of
225
Ac in radioimmunotherapy has been hampered due to its toxicity and lack of a suitable carrier which will deliver it to the targeted cells.
In an effort to reduce the toxicity of
225
Ac, numerous chelating agents such as, for example, 1,4,7,10-tetra-azacyclododecane-1,4,7,10-tetraacetic acid (DOTA), diethylenetriaminepentaacetic acid (DTPA), ethylene-diaminetetracetic acid (EDTA), 1,4,7,10,13-pentaazacyclopentadecane-1,4,7,10,13-pentaacetic acid (PEPA), and 1,4,7,10,13,16-hexaazacyclohexadecane-1,4,7,10,13,16-hexaacetic acid (HEHA) have been complexed with
225
Ac and evaluated in vivo for toxicity and stability. However, the toxicity of these complexes has proved to be still substantial.
G. J. Beyer et al, Isotoperpraxis, Vol. 26, pp. 111-114 (1990), has evaluated the in vivo uptake of
225
Ac-citrate and compared it to
169
Yb-citrate. This study has found that
225
Ac-citrate had more efficient blood clearance, greater liver uptake, and lower bone uptake than
169
Yb-citrate.
G. J. Beyer et al, Nucl. Med. & Biol., Vol. 24, pp. 367-372 (1997), has evaluated EDTMP (ethylenediaminetetramethylenephosphonic acid) as a chelant for
225
Ac. The study has found that EDTMP, depending on its concentration, reduces the liver uptake. However, the liver uptake of
225
Ac-EDTMP is still substantial and excretion of
225
Ac-EDTMP is poor. The study has also suggested that greater efficacy in endoradionuclide therapy of bone metastasis can be expected with the use of
225
Ac-EDTMP due to the alpha-radiation.
K. A. Deal et al, J. Med. Chem., Vol 42, pp. 298-2992 (1999), has evaluated biodistribution of a number of
225
Ac chelates. It has been observed that the structure of the chelant has a dramatic effect on the biodistribution of
225
Ac. HEHA (1,4,7,10,13,16-hexaazacyclohexadecane-1,4,7,10,13,16-hexaacetic acid) was the largest macrocyclic chelant.
225
Ac readily formed a complex with HEHA. Exceptional in vivo stability and reduced toxicity has been observed for
225
Ac-HEHA. This has been attributed to the large size and macrocyclic effect of HEHA.
Although various chelating agents were suggested and evaluated as carriers for
225
Ac, up to now
225
Ac has not been successfully chelated to an antibody and no successful therapeutic use of
225
Ac in animals or humans has been reported, presumably due to its inherent toxicity and/or stability problems of its complexes.
It would be desirable to provide complexes comprising
225
Ac and functionalized chelants which are kinetically and thermodynamically inert for use in therapeutic applications.
It would also be desirable to provide conjugates of such
225
Ac complexes with a biological carrier. The biological carrier in these conjugates would provide the tumor specificity and the
225
Ac isotope would provide potent cytotoxicity.
Another desirable property of these conjugates includes physiological compatibility which would permit the
225
Ac complex, if separated from its targeting, conjugated biological carrier in vivo, to be soluble in physiological fluids and thus be rapidly eliminated from the body.
The present invention is directed to
225
Ac complexes and their conjugates with a biological carrier. The
225
Ac complexes and conjugates of the present invention are useful for the treatment of cancer in mammals, especially humans.
More specifically, the present invention is directed to
225
Ac complexes comprising a functionalized polyazamacrocyclic chelant compound of the formula I hereinbelow:
G is independently hydrogen or
each Q is independently hydrogen, (CHR
5
)
p
CO
2
R or (CHR
5
)
p
PO
3
R
6
R
7
or
Q
1
is hydrogen, (CHR
5
)
w
CO
2
R or (CHR
5
)
w
PO
3
R
6
R
7
;
each R is independently hydrogen, benzyl or C
1
-C
4
alkyl;
R
6
and R
7
are independently H, C
1
-C
6
alkyl or (C
1
-C
2
alkyl)phenyl;
each R
5
is independently hydrogen; C
1
-C
4
alkyl or (C
1
-C
2
alkyl)phenyl;
with the proviso that at least two of the sum of Q and Q
1
must be other than hydrogen;
A is CH, N, C—Br, C—Cl, C—SO
3
H, C—OR
8
, C—OR
9
N
+
—R
10
X
−
, or
Z and Z
1
independently are CH, N, C—SO
3
H, N
+
—R
10
X
−
, C—CH
2
—OR
8
or C—C(O)—R
11
;
R
8
is H, C
1
-C
5
alkyl, benzyl, or benzyl substituted with at least one R
12
;
R
9
is C
1
-C
16
alkylamino;
R
10
is C
1
-C
16
alkyl, benzyl, or benzyl substituted with at least one R
12
;
R
11
is —O—(C
1
-C
3
alkyl), OH or NHR
13
;
R
12
is H, NO
2
, NH
2
, isothiocyanato, semicarbazido, thiosemicarbazido, maleimido, bromoacetamido or carboxyl;
R
13
is C
1
-C
5
alkyl;
X and Y are each independently hydrogen or may be taken with an adjacent X and Y to form an additional carbon—carbon bond;
n is 0 or 1;
m is an integer from 0 to 10 inclusive;
p is 1 or 2;
r is 0 or 1;
w is 0 or 1;
with the proviso that n is only 1 when X and/or Y form an additional carbon—carbon bond, and the sum of r and w is 0 or 1;
L is a linker/spacer group covalently bonded to, and replaces one hydrogen atom of one of the carbon a

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