scholarly journals A tumor-targeted immune checkpoint blocker

2019 ◽  
Vol 116 (32) ◽  
pp. 15889-15894 ◽  
Author(s):  
Yuhan Zhang ◽  
Changming Fang ◽  
Rongsheng E. Wang ◽  
Ying Wang ◽  
Hui Guo ◽  
...  
Keyword(s):  
Cell Death ◽  
Tumor Microenvironment ◽  
Bispecific Antibody ◽  
Checkpoint Inhibitors ◽  
Melanocortin 1 Receptor ◽  
Melanocyte Stimulating Hormone ◽  
Systemic Immune Activation ◽  
Parental Antibody ◽  
Stimulating Hormone

To direct checkpoint inhibition to the tumor microenvironment, while avoiding systemic immune activation, we have synthesized a bispecific antibody [norleucine4, d-Phe7]-melanocyte stimulating hormone (NDP-MSH)-antiprogrammed cell death-ligand 1 antibody (αPD-L1) by conjugating a melanocyte stimulating hormone (α-MSH) analog to the antiprogrammed cell death-ligand 1 to (αPD-L1) antibody avelumab. This bispecific antibody can bind to both the melanocortin-1 receptor (MC1R) and to PD-L1 expressed on melanoma cells and shows enhanced specific antitumor efficacy in a syngeneic B16-SIY melanoma mouse model compared with the parental antibody at a 5 mg/kg dose. Moreover, the bispecific antibody showed increased infiltrated T cells in the tumor microenvironment. These results suggest that a tumor-targeted PD-L1-blocking bispecific antibody could have a therapeutic advantage in vivo, especially when used in combination with other checkpoint inhibitors.

scholarly journals Synthesis of DOTA-pyridine chelates for 64Cu coordination and radiolabeling of αMSH peptide

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Hua Yang ◽  
Feng Gao ◽  
Brooke McNeil ◽  
Chengcheng Zhang ◽  
Zheliang Yuan ◽  
...  
Keyword(s):  
Full Potential ◽  
In Vivo Evaluation ◽  
Melanocortin 1 Receptor ◽  
Melanocyte Stimulating Hormone ◽  
Endogenous Copper ◽  
Coordination Ability ◽  
Copper Chelators ◽  
Cu Complexes ◽  
High Binding Affinity

Abstract Background 64Cu is one of the few radioisotopes that can be used for both imaging and therapy, enabling theranostics with identical chemical composition. Development of stable chelators is essential to harness the potential of this isotope, challenged by the presence of endogenous copper chelators. Pyridyl type chelators show good coordination ability with copper, prompting the present study of a series of chelates DOTA-xPy (x = 1–4) that sequentially substitute carboxyl moieties with pyridyl moieties on a DOTA backbone. Results We found that the presence of pyridyl groups significantly increases 64Cu labeling conversion yield, with DOTA-2Py, −3Py and -4Py quantitatively complexing 64Cu at room temperature within 5 min (1 × 10− 4 M). [64Cu]Cu-DOTA-xPy (x = 2–4) exhibited good stability in human serum up to 24 h. When challenged with 1000 eq. of NOTA, no transmetallation was observed for all three 64Cu complexes. DOTA-xPy (x = 1–3) were conjugated to a cyclized α-melanocyte-stimulating hormone (αMSH) peptide by using one of the pendant carboxyl groups as a bifunctional handle. [64Cu]Cu-DOTA-xPy-αMSH retained good serum stability (> 96% in 24 h) and showed high binding affinity (Ki = 2.1–3.7 nM) towards the melanocortin 1 receptor. Conclusion DOTA-xPy (x = 1–3) are promising chelators for 64Cu. Further in vivo evaluation is necessary to assess the full potential of these chelators as a tool to enable further theranostic radiopharmaceutical development.

Regulation of c-met expression in B16 murine melanoma cells by melanocyte stimulating hormone

1999 ◽  
Vol 112 (5) ◽  
pp. 623-630
Author(s):  
D. Rusciano ◽  
P. Lorenzoni ◽  
M.M. Burger
Keyword(s):  
Melanoma Cells ◽  
Parental Cell ◽  
Melanocortin Receptor ◽  
Parental Cell Line ◽  
Melanocyte Stimulating Hormone ◽  
Murine Melanoma ◽  
The One ◽  
Murine Melanoma Cells ◽  
Stimulating Hormone

B16 murine melanoma cells selected in vivo for enhanced liver metastatic ability (B16-LS9) show on the one hand an increased expression and constitutive activation of the proto-oncogene c-met (the receptor for hepatocyte growth factor/scatter factor), and on the other hand a more differentiated phenotype, when compared to the parental cell line, B16-F1. Following this observation, we have tried to establish whether there is a direct relationship between differentiation and c-met expression in B16 melanoma cells. Treatment of these cells with differentiating agents indicated that c-met expression was strongly induced by melanocyte stimulating hormone, while retinoic acid had almost no influence. c-met induction was triggered by engagement of the melanocortin receptor, cAMP elevation and PKA/PKC(α) activation, as respectively shown by the effects of ACTH, cAMP elevating agents and specific PK inhibitors. Regulation of c-met expression via the melanocortin receptor and cAMP raises the intriguing possibility that autocrine and/or paracrine mechanisms acting in vivo on this circuit might influence (through c-met expression and activation) the metastatic behavior of these tumor cells, which we have shown to be dependent on their c-met expression.

In vivo evaluation of 99mTc/188Re-labeled linear alpha-melanocyte stimulating hormone analogs for specific melanoma targeting

1999 ◽  
Vol 26 (6) ◽  
pp. 687-693 ◽  
Author(s):  
JianQing Chen ◽  
Michael F. Giblin ◽  
Nannan Wang ◽  
Silvia S. Jurisson ◽  
Thomas P. Quinn
Keyword(s):  
In Vivo Evaluation ◽  
Melanocyte Stimulating Hormone ◽  
Hormone Analogs ◽  
Stimulating Hormone

scholarly journals A novel mechanism in control of human pigmentation by β-melanocyte-stimulating hormone and 7-tetrahydrobiopterin

2005 ◽  
Vol 187 (2) ◽  
pp. 293-302 ◽  
Author(s):  
Jennifer D Spencer ◽  
Bhaven Chavan ◽  
Lee K Marles ◽  
Sobia Kauser ◽  
Hartmut Rokos ◽  
...  
Keyword(s):  
Opiate Receptor ◽  
Melanocortin 1 Receptor ◽  
Melanocyte Stimulating Hormone ◽  
Receptor Signal ◽  
Major Player ◽  
Key Enzyme ◽  
Μ Opiate Receptor ◽  
Inhibition Reaction ◽  
Stimulating Hormone

The human skin holds the full machinery for pro-opiomelanocortin processing. The α-melanocyte-stimulating hormone (α-MSH)/melanocortin-1-receptor cascade has been implicated as a major player via the cAMP signal in the control of melanogenesis. Only very recently the β-endorphin/μ-opiate receptor signal has been added to the list of regulators of melanocyte dendricity and melanin formation. In this context it was reported that (6R)-l-erythro-5,6,7,8-tetrahydrobiopterin (6BH4) can act as an allosteric inhibitor of tyrosinase, the key enzyme in melanogenesis, and this inhibition is reversible by both α- and β-MSH. It was also shown earlier that 7BH4, the isomer of 6BH4, is twice as active in this inhibition reaction. However, as yet it is not known whether 7BH4 is indeed present in loco in the melanosome. We here provide evidence that this isomer is present in this organelle in a concentration range up to 50 × 10−6 M. Determination of β-MSH in melanosomal extracts yielded 10 pg/mg protein. Moreover, we demonstrate reactivation of the 7BH4/tyrosinase inhibitor complex by β-MSH, whereas α-MSH failed to do so. Furthermore, we show intra-melanosomal l-dopa formation from dopachrome by 7BH4 in a concentration range up to 134 × 10−6 M. Based on these results, we propose a new receptor-independent mechanism in the control of tyrosinase/melanogenesis by β-MSH and the pterin 7BH4.

scholarly journals Synthesis of DOTA-Pyridine Chelates for 64Cu Coordination and Radiolabeling of αMSH Peptide

2020 ◽  
Author(s):  
Hua Yang ◽  
Feng Gao ◽  
Brooke McNeil ◽  
Chengcheng Zhang ◽  
Stefan Zeisler ◽  
...  
Keyword(s):  
Full Potential ◽  
In Vivo Evaluation ◽  
Melanocortin 1 Receptor ◽  
Melanocyte Stimulating Hormone ◽  
Endogenous Copper ◽  
Coordination Ability ◽  
Copper Chelators ◽  
Cu Complexes ◽  
High Binding Affinity

Abstract Background : 64Cu is one of the few radioisotopes that can be used for both imaging and therapy, enabling theranostics with identical chemical composition. Development of stable chelators is essential to harness the potential of this isotope, challenged by the presence of endogenous copper chelators. Pyridyl type chelators show good coordination ability with copper, prompting the present study of a series of chelates DOTA-xPy (x=1-4) that sequentially substitute carboxyl moieties with pyridyl moieties on a DOTA backbone. Results: We found that the presence of pyridyl groups significantly increases 64 Cu labeling yield, with DOTA-2Py, -3Py and -4Py quantitatively complexing 64 Cu at room temperature within 5 min (10 -4 M). [ 64 Cu]Cu-DOTA-xPy (x=2-4) exhibited good stability in human serum up to 24 hours. When challenged with 1000 eq. of NOTA, no transmetallation was observed for all three 64 Cu complexes. DOTA-xPy (x=1-3) were conjugated to a cyclized α-melanocyte-stimulating hormone (αMSH) peptide by using one of the pendant carboxyl groups as a bifunctional handle. [ 64 Cu]Cu-DOTA-xPy-αMSH retained good serum stability (>96% in 24 hours) and showed high binding affinity (Ki=2.1-3.7 nM) towards the melanocortin 1 receptor. Conclusion : DOTA-xPy (x=1-3) are promising chelators for 64 Cu. Further in vivo evaluation is necessary to assess the full potential of these chelators as a tool to enable further theranostic radiopharmaceutical development.

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