Low dose antibody-based methods for treating hematologic malignancies
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Publication Number
US-11292835-B2
Publication Date
2022-04-05
Expiration Date
Abstract
This invention provides a method for treating a subject afflicted with a hematologic malignancy comprising administering to the subject an agent targeting a hematologic malignancy-associated antigen, wherein the subject has a low peripheral cancerous cell burden. This invention also provides a method for treating a subject afflicted with a hematologic malignancy and having a high peripheral cancerous cell burden, comprising (i) medically lowering the subject's peripheral cancerous cell burden, and (ii) while the subject's peripheral cancerous cell burden is still low, administering to the subject an agent targeting a hematologic malignancy-associated antigen. Particularly envisioned are the subject methods for treating acute myeloid leukemia using an anti-CD33 antibody labeled with an alpha-emitting isotope, such as 225Ac-HuM195.
Core Innovation
The invention relates to treating a human subject afflicted with acute myeloid leukemia using 225Ac-labeled HuM195 that is administered intravenously. The subject selection is based on having a peripheral blast burden below 200 blast cells/b5l for one treatment approach and at or above 200 blast cells/b5l for another approach.
For subjects with peripheral blast burden below 200 blast cells/b5l, the document describes administering 225Ac-labeled HuM195 at specified doses and fractionation schedules. A low peripheral blast burden condition is maintained for dosing, and specific dose levels are administered in fractionated regimens, including fractions administered one week apart.
For subjects with peripheral blast burden at or above 200 blast cells/b5l, the document describes medically lowering the peripheral blast burden to below 200 blast cells/b5l first. Then, while the peripheral blast burden is still below 200 blast cells/b5l, 225Ac-labeled HuM195 is administered intravenously at specified dose levels, including options with fractions administered one week apart.
The document provides definitions for low and high burden and for sub-saturating dosing, including target-binding site to target antigens ratio. It also describes radiolabeled constructs and preparation elements for 225Ac-labeled HuM195 and includes phase 1 and phase 1/2 trial structures and response tables. Clinical trial outcomes reported in the document correlate responses with peripheral blast counts below 200/b5l, with no responses at peripheral blast counts at or above 200/b5l, and include significant reductions in blast burden.
Claims Coverage
The partial claims content includes two independent claims: one for subjects with peripheral blast burden below 200 blast cells/b5l and one for subjects with peripheral blast burden at or above 200 blast cells/b5l that is medically lowered to below 200 blast cells/b5l before dosing. Each independent claim is centered on intravenous administration of 225Ac-labeled HuM195 under a peripheral blast burden condition and at specified dose levels, with optional fractionated dosing where fractions are administered one week apart.
Intravenous administration of 225Ac-labeled HuM195 at a peripheral blast burden below 200 blast cells/b5l
Treating a human subject afflicted with acute myeloid leukemia by intravenously administering 225Ac-labeled HuM195 when the subject has a peripheral blast burden below 200 blast cells/b5l, with administration at specified doses including fractionated regimens in which the fractions are administered one week apart, or specified alternative dose options.
Medically lowering peripheral blast burden to below 200 blast cells/b5l and administering 225Ac-labeled HuM195 while still below 200 blast cells/b5l
Treating a human subject afflicted with acute myeloid leukemia and having a peripheral blast burden at or above 200 blast cells/b5l by medically lowering the peripheral blast burden to below 200 blast cells/b5l and, while the peripheral blast burden is still below 200 blast cells/b5l, intravenously administering 225Ac-labeled HuM195 at specified doses including options with fractions administered one week apart, or specified alternative dose options.
Across the independent claims, the inventive coverage is defined by treating acute myeloid leukemia with intravenous 225Ac-labeled HuM195 while enforcing a peripheral blast burden threshold (<200 blast cells/b5l) and applying specified dose levels that include fractionated regimens with fractions administered one week apart as an option.
Stated Advantages
Responses correlate with peripheral blast counts below 200/b5l, with no responses at 25200/b5l.
Significant reductions in blast burden are reported.
Documented Applications
Treatment of a human subject afflicted with acute myeloid leukemia based on peripheral blast burden categories (below 200 blast cells/b5l and at or above 200 blast cells/b5l) using 225Ac-labeled HuM195 and, for high-burden subjects, medically lowering peripheral blast burden before dosing.
Phase 1 and phase 1/2 clinical trial contexts are described, including reported response tables.
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