Preclinical pharmacokinetics of MFGR1877A, a human monoclonal antibody to FGFR3, and prediction of its efficacious clinical dose for the treatment of t(4;14)-positive multiple myeloma

Kamath, Amrita V.; Lü, Dan; Gupta, Priyanka; Jin, Denise; Yan, Xin; Brady, Ann; Stéphan, Jean-Philippe; Li, Hao; Tien, Janet; Jiang, Qing; Damico‐Beyer, Lisa A.

doi:10.1007/s00280-011-1807-5

Cited by 22 publications

(12 citation statements)

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“…Another approach to target FGFR3 directly is use of an anti-FGFR3 antibody. To date, antibodies targeting FGFR3 have been developed and shown to exhibit antitumor activity for FGFR3-associated multiple myeloma and bladder carcinoma (Trudel et al 2006, Hadari & Schlessinger 2009, Qing et al 2009, Kamath et al 2012. But antibody may carry a risk of an antibody-dependent cell cytotoxic reaction (Yamamoto et al 2010), which prevents its use in ACH.…”

Section: Introduction On Growth Plate Developmentmentioning

confidence: 99%

RECENT RESEARCH ON THE GROWTH PLATE: Advances in fibroblast growth factor signaling in growth plate development and disorders

Xie

Zhou

Chen

et al. 2014

Journal of Molecular Endocrinology

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Skeletons are formed through two distinct developmental actions, intramembranous ossification and endochondral ossification. During embryonic development, most bone is formed by endochondral ossification. The growth plate is the developmental center for endochondral ossification. Multiple signaling pathways participate in the regulation of endochondral ossification. Fibroblast growth factor (FGF)/FGF receptor (FGFR) signaling has been found to play a vital role in the development and maintenance of growth plates. Missense mutations in FGFs and FGFRs can cause multiple genetic skeletal diseases with disordered endochondral ossification. Clarifying the molecular mechanisms of FGFs/FGFRs signaling in skeletal development and genetic skeletal diseases will have implications for the development of therapies for FGF-signaling-related skeletal dysplasias and growth plate injuries. In this review, we summarize the recent advances in elucidating the role of FGFs/FGFRs signaling in growth plate development, genetic skeletal disorders, and the promising therapies for those genetic skeletal diseases resulting from FGFs/FGFRs dysfunction. Finally, we also examine the potential important research in this field in the future.

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Section: Introduction On Growth Plate Developmentmentioning

confidence: 99%

RECENT RESEARCH ON THE GROWTH PLATE: Advances in fibroblast growth factor signaling in growth plate development and disorders

Xie

Zhou

Chen

et al. 2014

Journal of Molecular Endocrinology

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“…Especially important is the t(4;14) translocation of FGFR3, which is cited as one of the most frequently mutated genes in MM, being found in approximately 15% of MM patients and associated with poor prognosis and chemotherapeutic resistance [69]. MFGR1877S is an IgG1 anti-FGFR3 mAb that has exhibited strong activity in mouse xenograft models of t(4;14)-positive MM [70]. A phase I study (NCT01122875) of MFGR1877S in t(4;14)-positive RRMM has been completed although no results have been published.…”

Section: Fgfr3mentioning

confidence: 99%

Monoclonal Antibodies for the Treatment of Multiple Myeloma: An Update

Abramson¹

2018

Preprint

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The past two decades have seen a revolution in multiple myeloma (MM) therapy with the introduction of several small molecules, mostly orally effective, whose mechanisms are based on proteasome inhibition, histone deacetylase (HDAC) blockade, and immunomodulation. Immunotherapeutic approaches to MM treatment using monoclonal antibodies (mAbs), while long in development, began to reap success with the identification of CD38 and SLAMF7 as suitable targets for development, culminating in the 2015 FDA approval of daratumumab and elotuzumab, respectively. This review highlights additional mAbs now in the developmental pipeline. Isatuximab, another anti-CD38 mAb, currently is under study in four phase III trials and may offer certain advantages over daratumumab. Several antibody-drug conjugates (ADCs) in the early stages of development are described, including JNJ-63723283, which has attained FDA breakthrough status for MM. Other mAbs described in this review include denosumab, recently approved for myeloma-associated bone loss, and checkpoint inhibitors, although the future status of the latter combined with immunomodulators has been clouded by unacceptably high death rates that caused the FDA to issue clinical holds on several of these trials. Also highlighted are therapies based on the B Cell Maturation Antigen (BCMA), another very promising target for anti-myeloma development.

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“…Indeed, at least three mice are usually sacrificed at each time point to get adequate sample and meet statistical requirements. 41) As a result, plenty of mice must be sacrificed to acquire a complete concentration-time profile in pharmacokinetics studies. Still, concentration versus time curves generated by samples from different animals may not accurately represent in vivo drug absorption.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of Geniposide by Monoclonal Antibody-Based icELISA in Mice after Oral Administration of Huanglian-Jiedu-Tang

Sun

et al. 2014

Biological & Pharmaceutical Bulletin

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Geniposide, Geniposide, the main active component in extracts of Gardenia jasminoides ELLIS., is one of the main components of Huanglian-Jiedu-Tang (HJT). This study aimed to validate an indirect competitive enzyme-linked immunosorbent assay (icELISA) based on monoclonal antibodies (mAb) against geniposide (anti-geniposide mAb), which was developed by our lab, and apply the assay to study the pharmacokinetics of geniposide in HJT in mice. Blood samples were drawn from mice at predetermined time points after oral administration of HJT in three dosages. A linear correlation was obtained for geniposide concentrations in the range from 1.17 to 37.50 µg/mL. The intra-day and inter-day precision values of the icELISA method were well within the recommended range (≤10%). The recovery rates ranged from 99.74 to 102.40%. Stability studies showed that geniposide sample solutions were intact for 12 h. The T max and mean residence time (MRT) of geniposide of the three groups were consistent with previous data. The results suggest that a reliable and effective method was established and could be applied to the study of the pharmacokinetics of geniposide in HJT.Key words geniposide; monoclonal antibody; pharmacokinetics; indirect competitive enzyme-linked immunosorbent assay; Huanglian-Jiedu-Tang; mouse Hanglian-Jiedu-Tang (HJT) is a famous traditional Chinese medicine (TCM) compound first described during the Tang Dynasty (Wai-Tai-Mi-Yao). HJT is composed of 4 Chinese herbs: Rhizoma Coptidis (Coptis chinensis FRANCH.), Radix Scutellariae (Scutellaria baicalensis GEORGI.), Cortex phellodendri (Phellodendron amurense RUPRECHT.) and Fructus Gardeniae (Gardenia jasminoides ELLIS.).1) In modern medicine, HJT is used to treat cardiovascular and cerebrovascular diseases, such as cerebral ischemia.2) Numerous recent studies have described several pharmacological characteristics of HJT, including antioxidant, [3][4][5] anti-inflammatory, 6,7) and neuroprotective activities. 8,9) Geniposide, an iridoid glycoside, is the major medical component of the Fructus Gardeniae 10) (Fig. 1). Geniposide can cross the blood-brain barrier, [11][12][13] which makes it a promising therapeutics for brain diseases. Geniposide can inhibit damage due to ischemia and limit memory impairment through its antioxidant 14) and antiinflammatory 15,16) activities. Therefore, geniposide is also one of the main components of HJT.Despite of the efficacy in indications has been proved by clinic; there are still adverse effect reports of geniposide. 17)Therefore, the effective measures for trace detecting are needed in the pharmacology studies of geniposide.Monoclonal antibodies (mAb) are immunoglobulins with high specificity and biological activity, 18) which have been extensively applied in prevention, diagnosis and treatment of diseases, detection of residues of pesticides and chloramphenicol in food samples, 19) and veterinary medicine development. The indirect competitive ELISA (icELISA), an immunological assay based on mAb, was reported to provide a valuable t...

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Preclinical pharmacokinetics of MFGR1877A, a human monoclonal antibody to FGFR3, and prediction of its efficacious clinical dose for the treatment of t(4;14)-positive multiple myeloma

Abstract: The predicted non-specific clearance of MFGR1877A in humans is similar to typical human IgG1 antibodies and will be verified in a Phase 1 study. The projected human efficacious dose and regimen appear to be achievable in patients.

Cited by 22 publications

References 19 publications

RECENT RESEARCH ON THE GROWTH PLATE: Advances in fibroblast growth factor signaling in growth plate development and disorders

RECENT RESEARCH ON THE GROWTH PLATE: Advances in fibroblast growth factor signaling in growth plate development and disorders

Monoclonal Antibodies for the Treatment of Multiple Myeloma: An Update

Pharmacokinetics of Geniposide by Monoclonal Antibody-Based icELISA in Mice after Oral Administration of Huanglian-Jiedu-Tang

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