A phase I trial of monoclonal antibody M195 in acute myelogenous leukemia: specific bone marrow targeting and internalization of radionuclide.

Scheinberg, David A.; Lovett, Dennis; Divgi, Chaitanya; Graham, Martin C.; Berman, Ellin; Pentlow, Keith S.; Feirt, Nikki; Finn, Ronald D.; Clarkson, Bayard D.; T, Gee

doi:10.1200/jco.1991.9.3.478

Cited by 200 publications

(88 citation statements)

References 22 publications

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“…Cell surface modulation with subsequent internalization of M195 antibody and conjugated isotope has been seen in vitro and in vivo in patients, and is an important aspect of its therapeutic effect in humans for the treatment of AML (10,11). Although Hd-IgG bound to the cell surface with .…”

Section: Resultsmentioning

confidence: 99%

“…The production of a CDR-grafted, humanized IgG1 construct (HuG1-M195) of the mouse M195 antibody, an anti-CD33 mAb that is specifically reactive with acute myelogenous leukemia (AML) cells and early myeloid progenitors, but not hematopoietic stem cells, has been described (6)(7)(8)(9). M195 is currently being evaluated in the therapy of AML (10,11). HuG1-M195 retains specificity of binding, the capability of internalization into HL60 leukemia cells, and the ability to fix human complement (7).…”

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confidence: 99%

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Engineered humanized dimeric forms of IgG are more effective antibodies.

Caron

Laird

et al. 1992

The Journal of Experimental Medicine

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SummaryHumanized IgG1 M195 (HuG1-M195), a complementarity determining region-grafted recombinant monoclonal antibody, is reactive with CD33, an antigen expressed on myelogenous leukemia cells. M195 is in use in trials for the therapy of acute myelogenous leukemia. Since biological activity of IgG may depend, in part, on multimeric Fab and Fc clustering, homodimeric forms of HuG1-M195 were constructed by introducing a mutation in the 3'1 chain CH3 region gene to change a serine to a cysteine, allowing interchain disulfide bond formation at the COOH terminal of the IgG. Despite similar avidity, the homodimeric IgG showed a dramatic improvement in the ability to internalize and retain radioisotope in target leukemia cells, Moreover, homodimers were 100-fold more potent at complement-mediated leukemia cell killing and antibody-dependent cellular cytotoxicity using human effectors. Therefore, genetically engineered multimeric constructs of IgG may have advantages relative to those forms that are found naturally.

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Engineered humanized dimeric forms of IgG are more effective antibodies.

Caron

Laird

et al. 1992

The Journal of Experimental Medicine

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“…The antibody HuM195, humanized version of the antibody M195 directed against CD33, has been developed and characterized by our group (5). M195 showed targeting to leukemia cells in humans (6) with the majority of the bound IgG being internalized into target cells in vivo (7,8). Based on this biology and pharmacokinetics, it has been proposed that mAb tagged with short-lived nuclides emitting short-ranged, high linear energy transfer (LET) alpha particles may be effective in therapy (9).…”

Section: Introductionmentioning

confidence: 99%

Influence of the Linker on the Biodistribution and Catabolism of Actinium-225 Self-Immolative Tumor-Targeted Isotope Generators

et al. 2006

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Current limitations to applications of monoclonal antibody (mAb) targeted isotope generators in radioimmunotherapy include the low mAb labeling yields and the non-specific radiation of normal tissues by non-targeted radioimmunoconjugates (RIC). Radiotoxicity occurs in normal organs that metabolize radiolabeled proteins and peptides, primarily liver and kidneys, or in radiosensitive organs with prolonged exposure to the isotope from the blood, such as the bone marrow. Actinium-225 nanogenerators also have the problem of released alpha emitting daughters. We developed two new bifunctional chelating agents (BCA) in order to address these issues. Thiol-maleimide conjugation chemistry was employed to increase the efficiency of the mAb radiolabelings by up to 8 fold. In addition, one bifunctional chelating agent incorporated a cleavable linker to alter the catabolism of the alpha particle emitting mAb conjugate. This linker was designed to be sensitive to cathepsins to allow release and clearance of the chelated radiometal after internalization of the radioimmunoconjugate into the cell. We compared the properties of the cleavable conjugate (mAb-DOTA-G3FC) to non-cleavable constructs (mAb-DOTA-NCS and mAb-DOTA-SH). The cleavable RIC was able to release 80% of its radioactive payload when incubated with purified cathepsin B. The catabolism of the constructs mAb-DOTA-G3FC and mAb-DOTA-NCS was investigated in vitro and in vivo. RIC integrity was retained at 85% over a period of 136 hours in mouse serum in vivo. Both conjugates were degraded over time inside HL-60 cells after internalization and in mouse liver in vivo. While we found that the rates of degradation of the two RICs in those conditions were similar, the amounts of the radiolabeled product residues were different. The cleavable mAb-DOTA-G3FC conjugate yielded a larger proportion of fragments below 6kDa in size in mouse liver in vivo after 12 hours than the DOTA-NCS conjugate. Biodistribution studies in mice showed that the mAb-DOTA-G3FC construct yielded a higher liver dose and prolonged liver retention of radioactivity compared to the mAb-DOTA-NCS conjugate. The accumulation in the liver seemed to be in part caused by the maleimide functionalization of the antibody, since the non-cleavable mAb-DOTA-SH maleimide-functionalized control conjugate displayed the same biodistribution pattern. These results provide an insight into the catabolism of RICs, by demonstrating that the release of the radioisotope from a RIC is not a sufficient condition to allow the radioactive moiety to clear from the body. The excretion mechanisms of radiolabeled fragments seem to constitute a major limiting step in the chain of events leading to their clearance.

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“…2,3 Interestingly, studies with radiolabeled anti-CD33 antibodies indicated that saturation of CD33 binding sites is generally achieved with doses around 5 mg/m 2 . 18,19 Furthermore, early studies indicated that surface CD33 levels return to pre-treatment levels within 72 h after anti-CD33 antibody administration despite internalization and modulation. 20,21 These two observations suggested the possibility that repeated administrations of lower doses of GO every three days may enhance intracellular delivery of the toxic calicheamicin-g 1 derivative relative to the biweekly administration schedule.…”

Section: Discussionmentioning

confidence: 99%