~50% TME is TAMS.TAMS is M2-Why Manocept has strategic advantage in targeting cancer! | NAVB Message Board Posts


Navidea Biopharmaceuticals, Inc.

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Msg  40537 of 40762  at  11/28/2023 1:13:34 AM  by

moneyonomics

The following message was updated on 11/28/2023 2:11:59 PM.

~50% TME is TAMS.TAMS is M2-Why Manocept has strategic advantage in targeting cancer!

    
with NAVB strategy  to
1- reprogram M2 to M1 using carbohydrate approved backbone and approved  therapeutic payloads while
2- concurrently reducing  CD47 SIPRa blocking while
3- blocking offsite targeting (repeat read of 2022 poster below)
 
Even though the following study out of China is analyzing possible non carbohydrate nanoparticles and payloads that can reprogram M2 to M1, it continues validating the facts that   ~50% of TME is TAMS and TAMS is M2, with the goal continuing to advance in oncology therapeutics to reprogram M2 to  M1,  further supporting the strategy of Manocept TME/TAMS oncology targeting concepts.
 
Modulating tumor-associated macrophages with natural nanomodulators by neutralizing acidic tumor microenvironment for tumor treatment
Lei Penga, Chenxu Zhanga, Guanlun Zhoua, Ao Yu*b,c and Yongjian Wang*a
 
 
Tumor-associated macrophages (TAMs) account for nearly half the mass of solid tumors. A wealth of research shows that TAMs are more similar to M2 macrophages, which have strong immunosuppressive activity. Manipulation of the phenotype of TAMs is a novel potential therapeutic approach to engage antitumor immunity.
 
Based on this, this paper comprehensively
reveals immunomodulator β-glucan (Glu) could not fully exert its role in reversing macrophage polarization under acidic conditions, and calcium carbonate increased the role of Glu by neutralizing acidic environment. To be specific, by constructing Glu and calcium carbonate co-precipitation system (Glu-VCC), the Glu-VCC can exhibit a stronger-immune activating effect through a cascade reaction with its ability to continuously regulate the tumor microenvironment. Glu-VCC nanoparticles can push the pH of the tumor tissue from 6.7 to 7.0 and increase M1-like macrophages by 57% compared to the limited reversal ability of Glu to TAMs. In addition, Glu-VCC showed excellent tumor clearance in in vivo experiments. These results not only expand the reach of calcium carbonate in the delivery of drugs but also provide new ideas for tumor immunotherapy....
 
 ...Introduction
Macrophages are very important immune cell types in the
human body, most of which are derived from bone marrow
monocytes.1 Under the guidance of different
microenvironmental signals, macrophages would polarize into two functional phenotypes, named classically activated macrophages (M1) and alternatively activated macrophages (M2).2 In contrast to the pro-inflammatory as well as tumoricidal effects of M1, M2 has anti-inflammatory and tumorigenic effects.3,4 Despite the complexity of the macrophage phenotype in the tumor microenvironment, it is evident that tumor-associated macrophages (TAMs) more closely resemble M2 macrophages. As a type of cell that owing adjustable polarity, M2-like TAM can be re-educated to a tumor-killing M1 type,5-7 providing an attractive target for cancer immunotherapy.8-13 To promote the transformation of TAMs into M1 macrophages, several reagents were applied to repolarize TAMs, such as monoclonal antibodies, kinase inhibitors and cytokine.14-16 Yeast-derived β-Glucan (Glu), a polysaccharide, is a potent immunomodulator that is shown to possess anticancer properties,17 and is proven to have the ability to reverse the TAMs (M2-like) into M1-like TAMs.18........
 
 
Navidea poster
 https://jitc.bmj.com/content/10/Suppl_2/A1204
1161 Synthetic CD206 targeted constructs carrying pacletaxel or novel bisphosphonate payloads alter macrophages towards pro-inflammatory phenotypes; the paclitaxel construct improves the efficacy of anti-CTLA4 in CT26 tumors
Free
  1. David Ralph,
  2. Jeffrey Arnold and
  3. Michael Rosol

Abstract

Background Tumor associated macrophages (TAMs) promote an immunosuppressive and protumor immune microenvironment reducing the efficacies of cancer immunotherapies. Altering TAM phenotypes from immunosuppressive to proinflammatory should stimulate TAMs directly and lymphocytes indirectly to attack cancer cells and potentially increase the efficacies of check point inhibitor therapies, like anti-CTLA4. Mannosylated Amine Dextrans (MADs) are synthetic ligands for CD206 that can carry small molecule payloads on degradable linkers to CD206 expressing cells, i.e. TAMs. Three MAD constructs were made carrying payloads of paclitaxel or one of two novel bisphosphonates and were evaluated in human GM-CSF macrophages for their abilities to durably alter macrophage phenotypes towards pro-inflammatory. The paclitaxel MAD was tested in the CT26 tumor model with or without anti-CTLA4.

Methods >Human monocytes from 3 donors were differentiated to CD206+ macrophages in GM-CSF supplemented RPMI1640 with 10% FBS (fresh medium) for 5 days.

>Medium was replaced with fresh media with varying concentrations of MAD + drug constructs or molar equivalents of free drugs or zoledronate and incubated for 24 hours.

>Saline or MAD without payload were controls.

>Drug containing media were replaced with fresh medium and incubated for 3 days (for durable responses)

>Cells were assessed by flow cytometry (MFI) for viability, CD206, CD163, CD80, CD86, MHC1, MHC2, SIRPalpha, and PD1.

>CT26 tumors implanted in Balb/c mice, treatment began when tumors were 100mm2.

>Mice treated with MAN-Paclitaxel (127 micrograms/dose), free paclitaxel, saline, or MAD no payload twice/week for 5 doses. Tumor volumes measured with calipers were the output.

Results Cell/FlowAssays

>None of the constructs reduced macrophage viability significantly.

>All three MAD-Drug constructs reduced expression of CD206 and CD163 (immunosuppression markers) and increased expression of CD80 and CD86 (pro-inflammatory markers).

>PD1 expression increased.

>MHC1 and MHC2 expression was not significantly changed.

>Both MAD-bisphosphonates – but not free drugs or MAD-paclitaxel – significantly reduced expression of SIRPalpha  (p<.0001).

CT26 Studies

>MAD-Paclitaxel and free paclitaxel were equally effective at tumor growth reduction.

>MAD-Paclitaxel plus anti-CTLA4 reduced tumor growth by 76%. Anti-CTLA4 alone by 52%.

Conclusions > All 3 MAD-drug constructs shifted macrophage phenotypes towards pro-inflammatory and more effectively the free drugs.

> Both MAD-Bisphosphonated constructs significantly reduced expression of SIRPalpha (checkpoint)

>MAD-paclitaxel and free paclitaxel increased the efficacy of anti-CTLA4, but

>CD206 targeted delivery can avoid off target toxicities of paclitaxel.

Shifting TAM phenotypes towards a pro-inflammatory state in a targeted fashion has the potential to increase the efficacies of other immunotherapies to reduce tumor burdens.

Acknowledgements Macrophage cell culture assays were performed at Discovery Life Sciences (Huntsville, AL). CT26/Balb/c studies were performed by Charles River Laboratories (North Carolina).

Ethics Approval All studies performed at Charles River Laboratories were reviewed and approved by an institutional IACUC committee.

 
 

 

 

 

 


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