Chimeric alkaline phosphatase-like proteins
Inventors
Raaben, Willem • Jonk, Luigi Johannes Cornelius • Van Den Berg, Erik Jan • Van Elsas, Andrea • MILLÁN, José Luis
Assignees
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Publication Number
US-9926544-B2
Publication Date
2018-03-27
Expiration Date
Abstract
The invention relates to improved alkaline phosphatases, pharmaceutical compositions comprising improved alkaline phosphatases and the use of improved alkaline phosphatases for preventing, treating or curing diseases.
Core Innovation
The invention relates to chimeric recombinant alkaline phosphatase-like proteins comprising a phosphatase activity. The described constructs include LVL-RecAP and related embodiments with a crown domain from human PLAP and catalytic flanking regions from human ALPI, together with specific amino-acid substitutions at positions 279, 328, and 478 (L, V, L). The proteins are presented as isolated protein embodiments defined by SEQ ID NOs.
The invention addresses zinc-deficiency-associated inflammatory and kidney disorders and hypophosphatasia, including the ability to provide zinc-independent phosphatase activity under conditions of low Zn2+ and in the presence of zinc chelators such as EDTA. The chimeric proteins are described as retaining activity when Zn2+ is depleted and as supporting PLP (pyridoxal 5′-phosphate) function, including binding kinetics and affinity comparisons.
The content further emphasizes comparative performance and functional outcomes, including increased zinc-independence, improved stability including heat stability, and favorable pharmacokinetics/organ targeting with higher organ/blood ratios compared with catALPI/crownALPP. The documented models include zinc chelator effects, renal protection in LPS-induced AKI, and reversal of hypophosphatasia phenotypes in Alpl−/− mouse models.
Claims Coverage
The provided claim set includes two independent claims. The inventive features focus on an isolated phosphatase-active protein defined by a specific amino-acid sequence and a pharmaceutical composition with specified fluid dosage forms.
Isolated phosphatase-active protein of SEQ ID NO: 1
An isolated protein having phosphatase activity comprising the amino acid sequence set forth in SEQ ID NO: 1.
Pharmaceutical composition in specified fluid forms
A composition wherein the fluid is an injectable fluid, an infusion fluid, an elixir, a syrup, or a suspension.
Across the independent claims provided, coverage is directed to an isolated phosphatase-active protein defined by SEQ ID NO: 1, and to pharmaceutical compositions in specified injectable, infusion, and other fluid dosage forms.
Stated Advantages
Increased zinc-independence, retaining activity under low Zn2+ and EDTA.
Improved stability, including enhanced heat stability.
Favorable pharmacokinetics/organ targeting with higher organ/blood ratios versus catALPI/crownALPP.
Therapeutic potential for zinc-deficiency-associated inflammatory and kidney disorders.
Therapeutic potential for hypophosphatasia, including reversal of hypophosphatasia phenotypes in Alpl−/− mouse models.
Documented Applications
Support for zinc-deficiency-associated inflammatory and kidney disorders.
Treatment of hypophosphatasia.
Renal protection in LPS-induced AKI in model contexts, including reduction of injury markers and functional deterioration.
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