Bayer Prolactin Receptor Antibody For Male And Female Pattern Hair Loss

[pegasus2]

@pegasus2 is approaching his late 70s though

I'll be dead before it's available

 

[Dimitri001]

For anyone young, like most on this forum, we probably don't have fibrosis and HMI will be good enough to give us a full head of hair till Stemson or other technologies get developed in the future.

Thats all that matters tbh

If it works and if it's out before we're in old folks' homes and if it's in our price range.

 

[LouisSarkozy]

such fibrosis that would prevent hmi from working is measurable in term of years ( 5+ years) or would it take a decade to be that bad to the point hmi won't work? thanks

 

[pegasus2]

such fibrosis that would prevent hmi from working is measurable in term of years ( 5+ years) or would it take a decade to be that bad to the point hmi won't work? thanks

Decades

 

[Chads don't bald]

If it works and if it's out before we're in old folks' homes and if it's in our price range.

Tbh aging itself will probably be under control by 2050 ish, so if you can survive till 2050 you can survive much longer (longevity escape velocity)

Or like that froggy dude always says, there's cryonics lol...

 

[pegasus2]

Acetylation modulates prolactin receptor dimerization​

Prolactin receptors: New mechanism may play role in cancer

If women had no prolactin receptors on cells in their mammary glands, they would not produce milk when they were nursing. Prolactin receptors are also found in other organs including the lung and the colon. The only problem is that these receptors are sort of like cellular wiring, and when the...

www.sciencedaily.com

Normally, a shared positive electrical charge and the resulting mutual repulsion keeps prolactin receptors from coming together. In their experiments, the team found that when prolactin binds to the receptors outside the cells, the acetylation neutralizes that charge on the receptors inside the cells, allowing the receptor molecules to come together, Chin said.


The more prolactin receptors a cell has, the more susceptible it is to this problem occurring, Chin said....One possibility will be developing monoclonal antibodies to target the prolactin receptors directly, he said.

Here, we report that in prolactin (PRL)-treated cells, PRL receptor (PRLR) undergoes cytoplasmic loop dimerization that is acetylation-dependent....PRLR dimerization and subsequent signaling are enhanced by treating the cells with deacetylase sirtuin (SIRT) inhibitor nicotinamide or histone deacetylase (HDAC) inhibitor trichostatin A but inhibited by expressing exogenous deacetylase SIRT2 or HDAC6. Our results suggest that acetylation and deacetylation provide the rheostat-like regulation for the cytokine receptor PRLR in its cytoplasmic loop dimerization and subsequent STAT5 activation.

the interaction between the PRLR cytoplasmic loop and full-length PRLR was inhibited by transient overexpression of the deacetylase SIRT2 or HDAC6 (Fig. 3B) or by depleting CBP with siRNA (Fig. 3C). Hence, PRLR cytoplasmic loop dimerization appears to be influenced by reversible acetylation.

HDAC4/9 are present in healthy hair follicles and this study reveals they are strongly associated with Androgenetic Alopecia. It was always assumed that this association was due to them being corepressors of the AR, but they are also corepressors of the PRLR.

Edit: HDAC4 may not be the causal gene at that locus, it may be Twist2 based on a new study.

The SNP with the smallest p value, apart from the Androgenetic Alopecia locus
on chromosome 20, (rs9287638 [A]: OR = 1.31, 95% CI = 1.21–
1.41, P = 1.01610212), is located on chromosome 2q37, with
seven other genome-wide significant SNPs in the same region.
These SNPs lie 558 kb downstream of HDAC4 (histone deacetylase
4). The next locus mapped within HDAC9 (histone deacetylase 9)
on chromosome 7p21.1 (rs2073963 [G]: OR = 1.29, 95%
CI = 1.20–1.38, P = 1.08610212). Our expression analysis re-
vealed that HDAC9 and HDAC4 were well expressed in hair
follicles (p = 6.5961023 and 2.6461023 respectively), and HDAC9
was not expressed in skin or scalp tissues

By interaction with transcription
factors ARR19 and CRIF1, HDAC4 plays a critical role in
inhibition of AR transactivation [24,25] and its accumulation
coincides with loss of androgen sensitivity in prostate cancer [26].
Furthermore, HDAC9 and HDAC4 share conserved residues and
their tissue specific expression pattern overlaps [27]. Very recently,
ZNF652 which has been shown to be involved in transcriptional
repression effect of HDACs [28] was identified to be a prostate
cancer susceptibility locus [29]. All together, our findings give rise
to the possibility that HDAC4 and HDAC9 might influence
pathogenesis of Androgenetic Alopecia through dysregulation of the androgen
pathway, highlighting a shared etiologic factor in this condition
and prostate cancer.

I think the balance of HDACs and HATs is skewed in Androgenetic Alopecia creating upregulation of AR and PRLR, which ultimately represses canonical Wnt signaling, causing a progressively shorter anagen phase. From the top SNPs in this study there is the AR of course, then genes that regulate AR and PRLR transactivation, PAX1 and TWIST which are involved in Wnt signaling and upregulated by PRLR. It certainly seems like Androgenetic Alopecia is driven by coactivation of the AR and PRLR. AR activation itself recruits histone acetyltransferases, which upregulate PRLR. Crosstalk between the two then takes place.

Similar to the cross-talk observed between PRLR and ER, other investigations have
found that PRLR-Stat5 signaling may also impact androgen
receptor (AR) function (27, 43). PRLR and AR can synergize
to induce gene transcription and cell survival in prostate
cancer cells (27, 43), whereas activated Stat5 and liganded
AR have been shown to directly associate and enhance the
nuclear localization of one another (27). This evidence
suggests that PRLR may lower the cellular threshold for
androgen-dependent physiologic responses.

https://clincancerres.aacrjournals.org/content/clincanres/19/7/1644.full.pdf

proteins that can directly deacetylate AR have been reported. Histone deacetylase 1 (HDAC1) has been shown to interact directly with the AR and repress AR activity [19]. It was observed that HDAC1 interacted with a region of the AR encompassing the DBD/LBD. Furthermore, the deacetylase activity of HDAC1 was required for AR repression and although not proven, the authors suggest that direct deacetylation of AR may result in a transcriptional switch during AR-dependent gene expression [19]. In support of this, both HDAC1 and TIP60 were found to occupy the PSA promoter suggesting that the balance between acetylation and deacetylation is crucial in AR gene regulation

ASC-J9 may be an ideal AR antagonist to use with HMI-115, as curcumin inhibits HATs.

https://sci-hub.se/https://www.tandfonline.com/doi/abs/10.1517/13543770902895727?journalCode=ietp20

HAT inhibitors have shown success in prostate cancer.

"A limited number of HAT inhibitors are in preclinical or clinical trials, with p300/CBP and P/CAF-specific inhibitors showing the most promising effects"

Androgen Receptor Signalling in Prostate Cancer: The Functional Consequences of Acetylation

The androgen receptor (AR) is a ligand activated transcription factor and member of the steroid hormone receptor (SHR) subfamily of nuclear receptors. In the early stages of prostate carcinogenesis, tumour growth is dependent on androgens, and AR directly ...

www.ncbi.nlm.nih.gov

prolactin genomic regions that exhibit deoxyribonuclease hypersensitivity, and confer hormone responsiveness, are most highly acetylated.

Estradiol promotes prolactin transactivation by inducing histone acetylation through ERα, but the predominant estrogen receptor in the scalp is ERβ and it silences ERα. So estradiol does not upregulate prolactin signaling in the hair follicle, despite upregulating it in other tissues.

Epigenetic Mechanisms in the Dopamine D2 Receptor-Dependent Inhibition of the Prolactin Gene

Abstract. Transcription of the prolactin gene is dynamically controlled by positive and negative hormone signals that target the regulatory promoter region. Bas

academic.oup.com

HDAC inhibitors also work for prostate cancer, through inhibiting HSP90.

Several HDAC inhibitors are currently undergoing testing in clinical trials including suberoylanilide hydroxamic acid (SAHA), LBH589 and Depsipeptide, although results suggest that these treatments have moderate effects [58, 61]. It may seem paradoxical that HDAC inhibitors are used as prostate cancer therapies since acetylation of AR increases cellular proliferation as outlined above. However, it has been proposed that HDAC inhibitors act via HDAC6 thus acetylating HSP90, known to be central in AR folding and ligand binding, or by sensitizing cells to DNA damage

One proposed mechanism is that HDAC inhibitors target HDAC6 which deacetylates HSP90 and decreases AR stability [55]. Furthermore, HDAC inhibitors directly suppress AR transcription [54,56].

Androgen Receptor Signalling in Prostate Cancer: The Functional Consequences of Acetylation

The androgen receptor (AR) is a ligand activated transcription factor and member of the steroid hormone receptor (SHR) subfamily of nuclear receptors. In the early stages of prostate carcinogenesis, tumour growth is dependent on androgens, and AR directly ...

www.ncbi.nlm.nih.gov

Prolactin actually upregulates HSP90

we identified the master chaperone, heat shock protein 90α (HSP90α), as a prolactin-Janus-Kinase-(JAK2)-signal-transducer-and-activator-of-transcription-5-(STAT5) target gene involved in survival, and here we investigated the role of HSP90 in the mechanism of prolactin-induced viability in response to DNA damage.

ATM Is Required for the Prolactin-Induced HSP90-Mediated Increase in Cellular Viability and Clonogenic Growth After DNA Damage | Request PDF

Request PDF | ATM Is Required for the Prolactin-Induced HSP90-Mediated Increase in Cellular Viability and Clonogenic Growth After DNA Damage | Prolactin acts as a survival factor for breast cancer cells, but the prolactin signaling pathway and the mechanism is unknown. Previously, we... | Find...

www.researchgate.net

It is theorized that in castration resistant prostate cancer AR activation is continued in part by "mechanisms including activation of kinase pathways that can both stabilize AR and enhance its transcriptional activity and upregulations of AR coactivators that increase AR mediated transcription. These sensitize AR to lower levels of ligand."

In addition to HER2, increased signaling by a number of other growth factor receptors (e.g, EGFR, IGF-1R, IL-6R) can enhance AR signaling and confer castration resistance in preclinical models [31–33]. These receptors induce downstream activation of critical growth and survival pathways, including the AKT, MAPK, and STAT pathways. Expression of both activated AKT and BRAF, also results in castration resistance [13]. While these mechanisms of CRPC are frequently referred to as “ligand independent”, it is unknown whether AR is truly activated without ligand binding or whether AR is sensitized to lower levels of ligands since experimental systems to decrease AR ligands, such as in vitro growth in charcoal stripped serum or castration of mice in vivo leave residual ligands. This distinction between true ligand independent and hypersensitized AR is not just semantic since therapies designed to further reduce AR ligands would be active only if ligand is still required. Furthermore, AR alleles containing mutations that impair ligand binding can no longer confer resistance to castration.

Another kinase implicated in AR crosstalk is SRC. Upon ligand binding, AR binds and activates SRC and downstream events within 5 minutes in a “non-genomic” mechanism [34]. SRC can in turn tyrosine phosphorylate AR augmenting its transcriptional activity. SRC activity is substantially increased in models of CRPC [35,36]. A 10 amino acid peptide that blocks the AR-SRC interaction inhibits androgen mediated proliferation in tissue culture and xenografts

Targeting the androgen receptor pathway in prostate cancer

When prostate cancers progress following androgen depletion therapy, there are currently few treatment options with only one, docetaxel, that has been shown to prolong life. Recent work has shown that castration resistant prostate cancers (CRPC) continue ...

www.ncbi.nlm.nih.gov

Prolactin upregulates all of these pathways that hypersensitize the AR.

Also of importance, HSP90 promotes transcription of Twist1. Twist1 ablation results in perpetual anagen phase in mice.

Inhibition of Heat Shock Protein 90 suppresses TWIST1 Transcription - PubMed

Molecular chaperone heat shock protein 90 (HSP90) is involved in oncogenic signaling pathways including epithelial-mesenchymal transition (EMT), a key process in tumor initiation, progression, metastasis, and chemoresistance. The molecular mechanisms underlying the involvement of HSP90 in EMT...

pubmed.ncbi.nlm.nih.gov

You can see from all this that the AR and PRLR are very interconnected. It's not hard to imagine that silencing the PRLR would stop the positive feedback loop between the two receptors and reverse male pattern baldness in a more potent and lasting way than current treatments, which is what was observed in stump-tailed macaques. Returning AR sensitivity to normal and restoring homeostasis could give lasting results that simple DHT inhibition does not.

 

[Matthewfakha]

Iam new to this forum
Is there any discord invite link?
Or any group buy

 

[RolfLeeBuckler]

After the last communication of HopeMedicine (19th ocotober 2021 产业基地启航！北大分子医学南京转化研究院产业发展基地正式启用 - 园区要闻 - 南京生物医药谷 (njbpv.cn)):

"Heqirui is an innovative biopharmaceutical company based on Professor Xiao Ruiping and his team from the School of Future Technology of Peking University, based on decades of research results in the field of translational medicine. At present, the company has completed the B round of financing, and signed a global exclusive license agreement with Bayer for the development and industrialization of the monoclonal antibody HMI-115 targeting the prolactin receptor (PRLR), and is developing and industrializing multiple indications worldwide change. This antibody has the function of promoting hair growth and has a therapeutic effect on hair loss. It has shown excellent characteristics in animal models and human safety, and has obtained the approval of the US FDA Phase II clinical trial. The US Phase II clinical trial will be launched in the near future. The patient is enrolled. In addition, Heqirui has also carried out the R&D and industrialization of more high-end innovative drugs through the dual-drive model of license-in (authorized introduction) and independent research and development."

i am now thinking that they wanted to tell us that the antibody has the potential to grow hair. But that the US Phase II clinical trial will be launched was only connected to the treatment of endometriosis i think. That is why they started the trial for Endometriosis in November. It isnt said that the hairloss trial would start also in the near future. They told only that THE US Phase II clinical trial (that means only 1 trial, NOT multiple clinical trials like they said in 2020) will be launched in the near future which has now been done with the endometriosis trial.

It seems like their goal only was to start a clinical trial with this monoclonal antibody HMI-115 which they have done now. It could now be a long time until the start trials for another conditions (hair loss)

 

[Numerous_Bet_3027]

After the last communication of HopeMedicine (19th ocotober 2021 产业基地启航！北大分子医学南京转化研究院产业发展基地正式启用 - 园区要闻 - 南京生物医药谷 (njbpv.cn)):

"Heqirui is an innovative biopharmaceutical company based on Professor Xiao Ruiping and his team from the School of Future Technology of Peking University, based on decades of research results in the field of translational medicine. At present, the company has completed the B round of financing, and signed a global exclusive license agreement with Bayer for the development and industrialization of the monoclonal antibody HMI-115 targeting the prolactin receptor (PRLR), and is developing and industrializing multiple indications worldwide change. This antibody has the function of promoting hair growth and has a therapeutic effect on hair loss. It has shown excellent characteristics in animal models and human safety, and has obtained the approval of the US FDA Phase II clinical trial. The US Phase II clinical trial will be launched in the near future. The patient is enrolled. In addition, Heqirui has also carried out the R&D and industrialization of more high-end innovative drugs through the dual-drive model of license-in (authorized introduction) and independent research and development."

i am now thinking that they wanted to tell us that the antibody has the potential to grow hair. But that the US Phase II clinical trial will be launched was only connected to the treatment of endometriosis i think. That is why they started the trial for Endometriosis in November. It isnt said that the hairloss trial would start also in the near future. They told only that THE US Phase II clinical trial (that means only 1 trial, NOT multiple clinical trials like they said in 2020) will be launched in the near future which has now been done with the endometriosis trial.

It seems like their goal only was to start a clinical trial with this monoclonal antibody HMI-115 which they have done now. It could now be a long time until the start trials for another conditions (hair loss)

Their goal was to start trials in multiple indications in 2021:

Hope Medicine Inc. Announced Dr. Henri Nico Doods as President and Head of Research & Clinical Development - PR Newswire APAC

SHANGHAI, Dec. 14, 2020 /PRNewswire/ -- Hope Medicine Inc. Announced Dr. Henri Nico Doods as President and Head of Research & Clinical Development

en.prnasia.com

"HMI-115, a prolactin receptor antibody, has passed animal experiments and phase I clinical human studies, and will enter phase II trials in multiple indications in 2021."

In this interview it was also mentioned that they want to start in Summer 2021:

和其瑞医药联合创始人肖瑞平：医药强国，吾辈使命 - 创新人才 - 南京生物医药谷

· 和其瑞医药有限公司联合创始人、董事长兼首席执行官；· 北京大学讲席教授，北大分子医学研究所所长；· 《新英格兰医学期刊》副主编

www.njbpv.cn

They have removed the information though, so they probably are just delayed.

 

[RolfLeeBuckler]

Their goal was to start trials in multiple indications in 2021:

Hope Medicine Inc. Announced Dr. Henri Nico Doods as President and Head of Research & Clinical Development - PR Newswire APAC

SHANGHAI, Dec. 14, 2020 /PRNewswire/ -- Hope Medicine Inc. Announced Dr. Henri Nico Doods as President and Head of Research & Clinical Development

en.prnasia.com

"HMI-115, a prolactin receptor antibody, has passed animal experiments and phase I clinical human studies, and will enter phase II trials in multiple indications in 2021."

In this interview it was also mentioned that they want to start in Summer 2021:

和其瑞医药联合创始人肖瑞平：医药强国，吾辈使命 - 创新人才 - 南京生物医药谷

· 和其瑞医药有限公司联合创始人、董事长兼首席执行官；· 北京大学讲席教授，北大分子医学研究所所长；· 《新英格兰医学期刊》副主编

www.njbpv.cn

They have removed the information though, so they probably are just delayed.

it is indeed very interesting that they at first mentioned in this article they want to start in summer 2021.
Then they secondly mentioned in this article that they want to start in 2021.
Now they removed also the 2021 date as a goal.

They were successfull with that in attracting investors. Congratulations to Xiu RUiping and Henri Nico Doods!

 

[badnewsbearer]

it is indeed very interesting that they at first mentioned in this article they want to start in summer 2021.
Then they secondly mentioned in this article that they want to start in 2021.
Now they removed also the 2021 date as a goal.

They were successfull with that in attracting investors. Congratulations to Xiu RUiping and Henri Nico Doods!

mh i wonder if anything happened during 2020 that turned out to be a lot longer lasting and damaging to the economy and the process of conducting in person clinical trials? must have been something major, of global proportions

 

[Matthewfakha]

Is there any group buy for this compound?

 

[Matthewfakha]

whatever it takes but where is this group buy on discord or where?

 

[Dimitri001]

Acetylation modulates prolactin receptor dimerization​

Prolactin receptors: New mechanism may play role in cancer

If women had no prolactin receptors on cells in their mammary glands, they would not produce milk when they were nursing. Prolactin receptors are also found in other organs including the lung and the colon. The only problem is that these receptors are sort of like cellular wiring, and when the...

www.sciencedaily.com

HDAC4/9 are present in healthy hair follicles and this study reveals they are strongly associated with Androgenetic Alopecia. It was always assumed that this association was due to them being corepressors of the AR, but they are also corepressors of the PRLR.





I think the balance of HDACs and HATs is skewed in Androgenetic Alopecia creating upregulation of AR and PRLR, which ultimately represses canonical Wnt signaling, causing a progressively shorter anagen phase. From the top SNPs in this study there is the AR of course, then genes that regulate AR and PRLR transactivation, PAX1 and TWIST which are involved in Wnt signaling and upregulated by PRLR. It certainly seems like Androgenetic Alopecia is driven by coactivation of the AR and PRLR. AR activation itself recruits histone acetyltransferases, which upregulate PRLR. Crosstalk between the two then takes place.

https://clincancerres.aacrjournals.org/content/clincanres/19/7/1644.full.pdf

ASC-J9 may be an ideal AR antagonist to use with HMI-115, as curcumin inhibits HATs.

https://sci-hub.se/https://www.tandfonline.com/doi/abs/10.1517/13543770902895727?journalCode=ietp20

HAT inhibitors have shown success in prostate cancer.

"A limited number of HAT inhibitors are in preclinical or clinical trials, with p300/CBP and P/CAF-specific inhibitors showing the most promising effects"

Androgen Receptor Signalling in Prostate Cancer: The Functional Consequences of Acetylation

The androgen receptor (AR) is a ligand activated transcription factor and member of the steroid hormone receptor (SHR) subfamily of nuclear receptors. In the early stages of prostate carcinogenesis, tumour growth is dependent on androgens, and AR directly ...

www.ncbi.nlm.nih.gov

This CREB binding protein inhibitor may be effective against Androgenetic Alopecia by inhibiting both AR and PRLR transactivation

Discovery of a selective catalytic p300/CBP inhibitor that targets lineage-specific tumours - Nature

A potent and selective catalytic inhibitor of p300/CBP histone acetyltransferases suppresses tumour proliferation across multiple cell lineages, illustrating the therapeutic potential of drug-like small molecules that target histone acetyltransferases.

www.nature.com

Estradiol promotes prolactin transactivation by inducing histone acetylation through ERα, but the predominant estrogen receptor in the scalp is ERβ and it silences ERα. So estradiol does not upregulate prolactin signaling in the hair follicle, despite upregulating it in other tissues.

Epigenetic Mechanisms in the Dopamine D2 Receptor-Dependent Inhibition of the Prolactin Gene

Abstract. Transcription of the prolactin gene is dynamically controlled by positive and negative hormone signals that target the regulatory promoter region. Bas

academic.oup.com

HDAC inhibitors also work for prostate cancer, through inhibiting HSP90.

Androgen Receptor Signalling in Prostate Cancer: The Functional Consequences of Acetylation

The androgen receptor (AR) is a ligand activated transcription factor and member of the steroid hormone receptor (SHR) subfamily of nuclear receptors. In the early stages of prostate carcinogenesis, tumour growth is dependent on androgens, and AR directly ...

www.ncbi.nlm.nih.gov

Prolactin actually upregulates HSP90

ATM Is Required for the Prolactin-Induced HSP90-Mediated Increase in Cellular Viability and Clonogenic Growth After DNA Damage | Request PDF

Request PDF | ATM Is Required for the Prolactin-Induced HSP90-Mediated Increase in Cellular Viability and Clonogenic Growth After DNA Damage | Prolactin acts as a survival factor for breast cancer cells, but the prolactin signaling pathway and the mechanism is unknown. Previously, we... | Find...

www.researchgate.net

It is theorized that in castration resistant prostate cancer AR activation is continued in part by "mechanisms including activation of kinase pathways that can both stabilize AR and enhance its transcriptional activity and upregulations of AR coactivators that increase AR mediated transcription. These sensitize AR to lower levels of ligand."

Targeting the androgen receptor pathway in prostate cancer

When prostate cancers progress following androgen depletion therapy, there are currently few treatment options with only one, docetaxel, that has been shown to prolong life. Recent work has shown that castration resistant prostate cancers (CRPC) continue ...

www.ncbi.nlm.nih.gov

Prolactin upregulates all of these pathways that hypersensitize the AR.


You can see from all this that the AR and PRLR are very interconnected. It's not hard to imagine that silencing the PRLR would stop the positive feedback loop between the two receptors and reverse male pattern baldness in a more potent and lasting way than current treatments, which is what was observed in stump-tailed macaques. Returning AR sensitivity to normal and restoring homeostasis could give lasting results that simple DHT inhibition does not.


Ultimate hair loss stack?: HMI-115, ASC-J9, Estriol. Nothing else needed for full reversal?

If only we could identify something downstream of PRLR activation that we could somehow target more cheaply and right now, without having to wait for HMI, which, who knows when it will become commercially available and whether it will be affordable.

 

[Dimitri001]

Is there any group buy for this compound?

I understand the Discord guys inquired about it with labs and were quoted an astronomical sum of money, as this thing is apparently hard to manufacture.

 

[pegasus2]

If only we could identify something downstream of PRLR activation that we could somehow target more cheaply and right now, without having to wait for HMI, which, who knows when it will become commercially available and whether it will be affordable.

Downstream targeting is also impossible at the moment. The best downstream target that might be doable before HMI would be Twist inhibition since that could be developed for treating cancer

 

[BaldingHell]

Downstream targeting is also impossible at the moment. The best downstream target that might be doable before HMI would be Twist inhibition since that could be developed for treating cancer

So do we have drug that do that?

 

[pegasus2]

So do we have drug that do that?

There is a patent for a Twist1 inhibiting peptide if you could find someone to make it. Hopefully there will be a small molecule inhibitor in the next couple years that will be easy to synthesize.

 

[Jackshtbro]

Paging @FollicleGuardian right now. We need you bro

Janey is banned bro

 

[BaldingHell]

There is a patent for a Twist1 inhibiting peptide if you could find someone to make it. Hopefully there will be a small molecule inhibitor in the next couple years that will be easy to synthesize.

Cant we use the patent details? Isnt what we always did in the GBs?