MGD007 compound specifially for advanced colorectal cancer

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boswind
Posts: 74
Joined: Fri Apr 11, 2014 12:04 pm

MGD007 compound specifially for advanced colorectal cancer

Postby boswind » Thu Nov 16, 2017 1:48 pm

is there anyone in the group who participated in phase I clinical trial of MGD007?

unlike PD-1 and PDL-1 inhibitors, MGD007 is to enhance T-cells to specifically target and kill tumor cells including their stem cells of colorectal cancers. so its mechanism is different from most immunology drugs approved by FDA.

For more info, you may want to view its phase I clinical trial and the website of Macrogenics.
01.24.14 Male, DX @54 Rectosigmoid Cancer, MRI: T3N0M0
03.19.14 Completed 5-week Radia+Xeloda
05.07.14 Had surgery
02.25.15 CT showed stage 4 inoperable
03.15 - 08.15, folfox + Avastin
08.15 - 07.17, 5FU+leucovorin+Avastin
07.17 - 01.18, Folfuri + Avastin
02.18 - 03.19, Centuximab + Irinotecan
03.19 - 05.19, Keytruda
05.19 - 9.19, Folfox+Avastin
10.19 -01.20: Centuximab+Irinotecan
03.20 - 06.20: STIVARGA
07.20 - present: lonsurf+Avanstin
MSS, KRAS wt, BRAF wt
131 rounds of chemos received (as of 12.31.20)

NHMike
Posts: 2555
Joined: Fri Jul 21, 2017 3:43 am

Re: MGD007 compound specifially for advanced colorectal cancer

Postby NHMike » Thu Nov 16, 2017 2:55 pm

Glycoprotein A33 (gpA33) is a 43 kDa membrane-bound glycoprotein with expression restricted to the surface of normal human colon and small bowel epithelial cells. In addition, the gpA33 antigen is homogeneously expressed at high levels in > 95% of primary and metastatic human CRC. These observations suggest that gpA33 that could be an attractive target for the immunotherapy of CRC. The Dual-Affinity Re-Targeting (DART®) technology, is a proprietary antibody-based platform that has been designed to engage multiple targets with a single molecule. MGD007 is a novel gpA33x CD3 DART protein that targets gpA33-positive cells for recognition and elimination by co-engagement of CD3-expressing T lymphocytes. MGD007 mediates redirected T cell killing of gpA33-expressing CRC cell lines in vitro and regression of transplantable CRC cell line xenografts in preclinical tumor models. Preclinical toxicology studies in cynomolgus monkeys demonstrated that MGD007 could be administered safely with a pharmacokinetic profile supportive of repeat dosing on a weekly basis.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4288761/

It appears that they found something common to the vast majority of CRCs that sits on the surface of the cell. My son told me that the problem with KRAS is that the molecule sits inside the cell so you can't attack it with immunotherapy approaches. This sounds like a promising idea if the gpA33 antigen isn't found in healthy cells too.
6/17: ER rectal bleeding; Colonoscopy
7/17: 3B rectal. T3N1bM0. 5.2 4.5 4.3 cm. Lymphs: 6 x 4 mm, 8 x 6, 5 x 5
7/17-9/17: Xeloda radiation
7/5: CEA 2.7; 8/16: 1.9; 11/30: 0.6; 12/20 1.4; 1/10 1.8; 1/31 2.2; 2/28 2.6; 4/10 2.8; 5/1 2.8; 5/29 3.2; 7/13 4.5; 8/9 2.8, 2/12 1.2
MSS, KRAS G12D
10/17: 2.7 2.2 1.6 cm (-90%). Lymphs: 3 x 3 mm (-62.5%), 4 x 3 (-75%), 5 x 3 (-40%). 5.1 CM from AV
10/17: LAR, Temp Ileostomy, Path Complete Response
CapeOx (8) 12/17-6/18
7/18: Reversal, Port Removal
2/19: Clean CT

boswind
Posts: 74
Joined: Fri Apr 11, 2014 12:04 pm

Re: MGD007 compound specifially for advanced colorectal cancer

Postby boswind » Fri Nov 17, 2017 11:51 am

It indeed looks very promising. I feel the mechanism is better and may be safer than Roche's immu-compound in clinical trials which targets on CEA.
01.24.14 Male, DX @54 Rectosigmoid Cancer, MRI: T3N0M0
03.19.14 Completed 5-week Radia+Xeloda
05.07.14 Had surgery
02.25.15 CT showed stage 4 inoperable
03.15 - 08.15, folfox + Avastin
08.15 - 07.17, 5FU+leucovorin+Avastin
07.17 - 01.18, Folfuri + Avastin
02.18 - 03.19, Centuximab + Irinotecan
03.19 - 05.19, Keytruda
05.19 - 9.19, Folfox+Avastin
10.19 -01.20: Centuximab+Irinotecan
03.20 - 06.20: STIVARGA
07.20 - present: lonsurf+Avanstin
MSS, KRAS wt, BRAF wt
131 rounds of chemos received (as of 12.31.20)

boswind
Posts: 74
Joined: Fri Apr 11, 2014 12:04 pm

Re: MGD007 compound specifially for advanced colorectal cancer

Postby boswind » Fri Nov 17, 2017 3:32 pm

https://www.google.com/url?sa=t&rct=j&q ... 1sAPMYKo_8

In Feb 2016 Morgan Stanley assessed Macrogenics the maker of MGD007. The following paragraph is about their optimistic view of Macrogenics' propriety DART technology.
---
DARTs represent the potential major upside driver to our valuation:
Mgt. has 5 DARTs currently in clinical testing, with initial data on at least two of
the targets (and potentially three) in 2016. We see the CD3/CD19 DART, which
has the same target as Amgen's Blincyto and CAR-T, and the CD3/CD123
DARTs as the most promising. Importantly, mgt. has improved upon prior
bispecific platforms by increasing DART half-lives to prevent continuous
infusions and improving manufacture. This being said, while initial data could
offer a first look at safety and some efficacy, we may need to await more
robust data in 2017 before the efficacy signal is known.
--

Hopefully Morgan Stanley will publish an updated report soon.
---
We need initial DART data to get more bullish: Core to our thesis is solid
DART data that would allow us to value the opportunity across targets and
diseases. Thus, while we remain optimistic on bispecifics as a therapeutic
approach and believe that MacroGenics has developed a suitable platform for
their development, initial data is key to our ability to value the program. We
await clear efficacy data from the platform.
---
01.24.14 Male, DX @54 Rectosigmoid Cancer, MRI: T3N0M0
03.19.14 Completed 5-week Radia+Xeloda
05.07.14 Had surgery
02.25.15 CT showed stage 4 inoperable
03.15 - 08.15, folfox + Avastin
08.15 - 07.17, 5FU+leucovorin+Avastin
07.17 - 01.18, Folfuri + Avastin
02.18 - 03.19, Centuximab + Irinotecan
03.19 - 05.19, Keytruda
05.19 - 9.19, Folfox+Avastin
10.19 -01.20: Centuximab+Irinotecan
03.20 - 06.20: STIVARGA
07.20 - present: lonsurf+Avanstin
MSS, KRAS wt, BRAF wt
131 rounds of chemos received (as of 12.31.20)

jortego128
Posts: 288
Joined: Sat Aug 15, 2015 7:47 am

Re: MGD007 compound specifially for advanced colorectal cancer

Postby jortego128 » Fri Nov 17, 2017 5:29 pm

Im pretty sure we had a member here who was on an MGD0007 trial, she was young and had young children. I dont remember her name but I think she was on the 2015 Colondar? The name Lindsey comes to mind. In any case, she had a partial response, but then she either had progression or the drug became toxic, dont remember which.

Josh
DM 57 yrs old dx 6/8/15 T:4a N:1b M:1
KRAS G12D and TP53 C242fs mutations
Poorly Differentiated, Prominent Signet Ring Component(~50%)
Microsatellite Stable, 3 of (13)lymph nodes positive
15 Liver mets, largest 3.2 cm
Prim. Resection, Right Hemicolectomy 6/21/15
Start Chemo 7/20/15
2 rounds FOLFOX, 1 round FOLFOX +Avastin
CT 8/28/15, met growth, largest 4.5cm
4 rounds FOLFOX+Avastin
CT 11/06/15 mets stable, lungs clear
Begin FOLFIRI+Avastin 11/17/15, Stop chemo 1/26/16
Entered Paradise 3/11/2016

NHMike
Posts: 2555
Joined: Fri Jul 21, 2017 3:43 am

Re: MGD007 compound specifially for advanced colorectal cancer

Postby NHMike » Fri Nov 17, 2017 6:44 pm

jortego128 wrote:Im pretty sure we had a member here who was on an MGD0007 trial, she was young and had young children. I dont remember her name but I think she was on the 2015 Colondar? The name Lindsey comes to mind. In any case, she had a partial response, but then she either had progression or the drug became toxic, dont remember which.

Josh


They theoretically have the dosages straightened out though as it's in Phase III. It sounds most promising if they can identify cancer cells from the cell surface.
6/17: ER rectal bleeding; Colonoscopy
7/17: 3B rectal. T3N1bM0. 5.2 4.5 4.3 cm. Lymphs: 6 x 4 mm, 8 x 6, 5 x 5
7/17-9/17: Xeloda radiation
7/5: CEA 2.7; 8/16: 1.9; 11/30: 0.6; 12/20 1.4; 1/10 1.8; 1/31 2.2; 2/28 2.6; 4/10 2.8; 5/1 2.8; 5/29 3.2; 7/13 4.5; 8/9 2.8, 2/12 1.2
MSS, KRAS G12D
10/17: 2.7 2.2 1.6 cm (-90%). Lymphs: 3 x 3 mm (-62.5%), 4 x 3 (-75%), 5 x 3 (-40%). 5.1 CM from AV
10/17: LAR, Temp Ileostomy, Path Complete Response
CapeOx (8) 12/17-6/18
7/18: Reversal, Port Removal
2/19: Clean CT

boswind
Posts: 74
Joined: Fri Apr 11, 2014 12:04 pm

Re: MGD007 compound specifially for advanced colorectal cancer

Postby boswind » Fri Nov 17, 2017 7:51 pm

NHMike wrote:
They theoretically have the dosages straightened out though as it's in Phase III. It sounds most promising if they can identify cancer cells from the cell surface.

It is still in Phase I, which will end in 2019.

I just did key word search on this forum and found many messages posted in 2015 about MGD007 and DK made a lot of good comments. The bad thing I found is its toxicity because normal GI-cells also have gpA33 that MGD007 targets on.

I am trying to get latest data about its efficiency through my network.
01.24.14 Male, DX @54 Rectosigmoid Cancer, MRI: T3N0M0
03.19.14 Completed 5-week Radia+Xeloda
05.07.14 Had surgery
02.25.15 CT showed stage 4 inoperable
03.15 - 08.15, folfox + Avastin
08.15 - 07.17, 5FU+leucovorin+Avastin
07.17 - 01.18, Folfuri + Avastin
02.18 - 03.19, Centuximab + Irinotecan
03.19 - 05.19, Keytruda
05.19 - 9.19, Folfox+Avastin
10.19 -01.20: Centuximab+Irinotecan
03.20 - 06.20: STIVARGA
07.20 - present: lonsurf+Avanstin
MSS, KRAS wt, BRAF wt
131 rounds of chemos received (as of 12.31.20)

NHMike
Posts: 2555
Joined: Fri Jul 21, 2017 3:43 am

Re: MGD007 compound specifially for advanced colorectal cancer

Postby NHMike » Sat Nov 18, 2017 6:35 am

boswind wrote:
NHMike wrote:
They theoretically have the dosages straightened out though as it's in Phase III. It sounds most promising if they can identify cancer cells from the cell surface.

It is still in Phase I, which will end in 2019.

I just did key word search on this forum and found many messages posted in 2015 about MGD007 and DK made a lot of good comments. The bad thing I found is its toxicity because normal GI-cells also have gpA33 that MGD007 targets on.

I am trying to get latest data about its efficiency through my network.


We were wondering if it attacked non-cancerous cells and it looks like it does that.
6/17: ER rectal bleeding; Colonoscopy
7/17: 3B rectal. T3N1bM0. 5.2 4.5 4.3 cm. Lymphs: 6 x 4 mm, 8 x 6, 5 x 5
7/17-9/17: Xeloda radiation
7/5: CEA 2.7; 8/16: 1.9; 11/30: 0.6; 12/20 1.4; 1/10 1.8; 1/31 2.2; 2/28 2.6; 4/10 2.8; 5/1 2.8; 5/29 3.2; 7/13 4.5; 8/9 2.8, 2/12 1.2
MSS, KRAS G12D
10/17: 2.7 2.2 1.6 cm (-90%). Lymphs: 3 x 3 mm (-62.5%), 4 x 3 (-75%), 5 x 3 (-40%). 5.1 CM from AV
10/17: LAR, Temp Ileostomy, Path Complete Response
CapeOx (8) 12/17-6/18
7/18: Reversal, Port Removal
2/19: Clean CT

boswind
Posts: 74
Joined: Fri Apr 11, 2014 12:04 pm

Re: MGD007 compound specifially for advanced colorectal cancer

Postby boswind » Thu Nov 23, 2017 10:27 am

Happy Thanksgiving!

Below are three pieces of dated info related to MGD007. The info was obtained from reliable sources via my network.

December 14, 2016
Progress of MGD006 and MGD007 studies slowed by on-target toxicities; refined toxicity management protocols and clinical activity should allow for continued development. MACROGENICS discussed evolution of its protocol for managing cytokine release syndrome, which is the primary (and expected) toxicity observed for MGD006. Continued dose-escalation is proceeding that is leveraging insight from CRS management protocols developed from CAR-T studies. Evidence of clinical activity has been observed in three patients with blast count reductions. Reversible GI toxicity has been observed in the Ph 1 study of MGD007, which MACROGENICS believes is due to on-target activity and local release of cytokines. MACROGENICS has also evolved its supportive care strategy and is continuing dose escalation, with evidence of dose-dependent biomarker activity observed thus far.


24 Jan 2017
We are pushing out assumed launches for the DARTs MGD006 and MGD007 to 2023 (vs. 2022 previously) given slower than expected dose escalation progress ─ Recall at the company's R&D Day in Dec '16 dose escalation for MGD006 (CD123xCD3) and MGD007 (gpA33xCD3) had progressed more slowly than expected.


November 9, 2017
MGD007 (gpA33x CD3): According to management, the dose escalation portion from the ongoing Phase I study has been completed, with various expansion cohorts ongoing with the goal to define an optimal dose and schedule. Data wise, on-target gastro-intestinal (GI) tract adverse events were observed in the study, with the application of steroids to the GI tract appearing to improve patient tolerability. Moving forward, an update from this study is expected at the 2018 AACR or ASCO meeting.
01.24.14 Male, DX @54 Rectosigmoid Cancer, MRI: T3N0M0
03.19.14 Completed 5-week Radia+Xeloda
05.07.14 Had surgery
02.25.15 CT showed stage 4 inoperable
03.15 - 08.15, folfox + Avastin
08.15 - 07.17, 5FU+leucovorin+Avastin
07.17 - 01.18, Folfuri + Avastin
02.18 - 03.19, Centuximab + Irinotecan
03.19 - 05.19, Keytruda
05.19 - 9.19, Folfox+Avastin
10.19 -01.20: Centuximab+Irinotecan
03.20 - 06.20: STIVARGA
07.20 - present: lonsurf+Avanstin
MSS, KRAS wt, BRAF wt
131 rounds of chemos received (as of 12.31.20)


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