Mutations in the Catalytic Domain of Human Matrix Metalloproteinase-1 (MMP-1) That Allow for Regulated Activity through the Use of Ca2+

Paladini, Rudolph D.; Ge, Wei; Kundu, Anirban; Zhao, Qiping; Bookbinder, Louis H.; Keller, G A; Shepard, H. Michael; Frost, Gregory I.

doi:10.1074/jbc.m112.364729

Cited by 9 publications

(6 citation statements)

References 36 publications

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“…A key characteristic of the TME is acidic pH e (below pH7), resulting, in large part, from increased lactic acid concentrations from glycolytic metabolism (Warburg effect) ( 46 , 72 ). Our preliminary exploration in other disease areas indicates that PaCS may also underpin the differential binding activities of the different ApoE isoforms (ApE2, ApoE3, and ApoE4) to amyloid-β ( 1 – 40 ) peptide in a pH-dependent manner. These observations suggest the possible involvement of PaCS in the pathogenesis of Alzheimer disease.…”

Section: Discussionmentioning

confidence: 95%

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Generating tumor-selective conditionally active biologic anti-CTLA4 antibodies via protein-associated chemical switches

Chang

Frey

Liu

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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Anticytotoxic T lymphocyte-associated protein 4 (CTLA4) antibodies have shown potent antitumor activity, but systemic immune activation leads to severe immune-related adverse events, limiting clinical usage. We developed novel, conditionally active biologic (CAB) anti-CTLA4 antibodies that are active only in the acidic tumor microenvironment. In healthy tissue, this binding is reversibly inhibited by a novel mechanism using physiological chemicals as protein-associated chemical switches (PaCS). No enzymes or potentially immunogenic covalent modifications to the antibody are required for activation in the tumor. The novel anti-CTLA4 antibodies show similar efficacy in animal models compared to an analog of a marketed anti-CTLA4 biologic, but have markedly reduced toxicity in nonhuman primates (in combination with an anti-PD1 checkpoint inhibitor), indicating a widened therapeutic index (TI). The PaCS encompass mechanisms that are applicable to a wide array of antibody formats (e.g., ADC, bispecifics) and antigens. Examples shown here include antibodies to EpCAM, Her2, Nectin4, CD73, and CD3. Existing antibodies can be engineered readily to be made sensitive to PaCS, and the inhibitory activity can be optimized for each antigen’s varying expression level and tissue distribution. PaCS can modulate diverse physiological molecular interactions and are applicable to various pathologic conditions, enabling differential CAB antibody activities in normal versus disease microenvironments.

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Section: Discussionmentioning

confidence: 95%

“…Analogous approaches were utilized previously to increase the useful window of activity in microbes, plants, and humans for a wide range of effects, including processing efficiencies, maintaining yields ( 34 ), and improving drug delivery (cited in the acknowledgments of ref. 38 ).…”

mentioning

confidence: 99%

Generating tumor-selective conditionally active biologic anti-CTLA4 antibodies via protein-associated chemical switches

Chang

Frey

Liu

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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“…These fragments can also be degraded by other MMPs into CTX-II. [ 21 – 26 ] The CTX-II is released into the serum and urine, and the CTX-II concentration in body fluids reflects OA progression. [ 27 ] Studies showed that serum CTX-II can be used to monitor the OA progression.…”

Section: Discussionmentioning

confidence: 99%

Comparative study of CTX-II, Zn2+, and Ca2+ from the urine for knee osteoarthritis patients and healthy individuals

Xin

et al. 2017

Medicine

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The aim of the study was to explore the relationship between the concentration of C-telopeptide fragments of type II collagen (CTX-II), Zn2+, and Ca2+ in urine and knee osteoarthritis (KOA).Eighty-two patients with KOA and 20 healthy volunteers were enrolled. Anteroposterior and lateral position x-rays of knee joints were collected. The images were classified according to Kellgren-Lawrence radiographic grading criterion. The patients were divided into group grade I, group grade II, group grade III, and grade IV. The concentration of CTX-II in the urine was detected by enzyme-linked immunosorbent assay. The concentration of Zn2+ and Ca2+ in urine was detected by inductively coupled plasma atomic emission spectrometry.Compared with the healthy individuals, the concentration of CTX-II was significantly higher in KOA patients. The concentration of CTX-II in KOA patients from high to low was as follows: group IV, group III, group II, and group I. There was no significant difference between group I and healthy individuals. The concentration of Zn2+ and Ca2+ in urine of KOA patients was higher than that in healthy individuals. There was no difference in each KOA group.The concentration of CTX-II is instrumental to diagnose the progress of KOA. The concentration of Zn2+ and Ca2+ in urine is helpful for early diagnosis of KOA.

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“…To investigate whether the enzymatic activity of MMP-26 is involved directly in GDF15 processing, various catalytically inactive mutants of MMP-26 were generated by deleting the zinc-binding motif (Flag-MMP26‚208 -219), or by mutating the His (Flag-MMP26-H208A) or the Glu (Flag-MMP26-E209A) residue in the zinc-binding motif (HEIGHSLGLQHS) to Ala ( Figure 3A). These mutations had previously been shown to be able to affect the catalytic activities of various MMP members (21)(22)(23). The mutation sites for MMP-26 were selected according to the sequence conservation among these MMP members.…”

Section: Enzymatic Activity Of Mmp-26 Is Required For Processing Gdf15mentioning

confidence: 99%

Maturation of Growth Differentiation Factor 15 in Human Placental Trophoblast Cells Depends on the Interaction With Matrix Metalloproteinase-26

Li¹,

Wang

Cao

et al. 2014

The Journal of Clinical Endocrinology & Metabolism

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Mutations in the Catalytic Domain of Human Matrix Metalloproteinase-1 (MMP-1) That Allow for Regulated Activity through the Use of Ca2+

Cited by 9 publications

References 36 publications

Generating tumor-selective conditionally active biologic anti-CTLA4 antibodies via protein-associated chemical switches

Generating tumor-selective conditionally active biologic anti-CTLA4 antibodies via protein-associated chemical switches

Comparative study of CTX-II, Zn2+, and Ca2+ from the urine for knee osteoarthritis patients and healthy individuals

Maturation of Growth Differentiation Factor 15 in Human Placental Trophoblast Cells Depends on the Interaction With Matrix Metalloproteinase-26

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