Antibody Drug Conjugates – trial is recruiting in several places

Hey Artie!  Hope you are feeling better????!  Yes, this trial is using glembatumumab vedotin, which links auristatin to the glycoprotein NMB [GPNMB], the Celldex product.  In case folks don't know much about ADC's and what they are….here is something I researched for a friend of mine who participated in the Genentech ADC trial (where auristatin was linked to endothelian B) over a year ago.

1.  ADC (Antibody-Drug Conjugate) = Trojan horse therapy, in which a target antibody is attached via a linker to a cytotoxic agent.  This technique takes a bad news cytotoxin like auristatin, attaches it via a special molecule to a monocolonal antibody that targets antigens preferentially expressed on the surface of targeted cancer cells, in this case – endothelian B, and then sneaks the cytotoxic agent into the targeted tumor cell with no horrible side effects to the rest of the body.  Has been in the works since the 80's. Over that time laboratory researchers have found many more possible monoclonal antibodies to use (and studied which tumors express them the most) and a variety of gradually improving techniques to "link" the chemotherapeutic agent to the antibody.  Improved "linkers" seem to have made it easier to use a variety of antibodies as well as cytotoxic agents and keep the whole little trifecta intact until it reaches its destination. 

2.  Endothelin receptor ETB (Genentech's RG-7636) as well as Glembatumumab vedotin (Celldex's ADC using the receptor GPNMB) are the only two ADC products I can find used against melanoma.  Celldex seems to have withdrawn its product from that line of attack and is focusing its use on breast cancer only at this time.  Though, Sievers paper (Seattle Genentech) reports: "In a phase I/II trial in patients with unresectable late-stage melanoma, CDX-011 (yet another name for Glembatumumab vedotin) showed overall response rates ranging from 14% to 19% depending on dosing frequency and GPNMB expression levels."

3.  Endothelin receptor ETB is apparently expressed on most melanoma tumors (as well as in skin cells in general…and is even in the pathway for their embryonic development).  So much so…that at first folks tried the drug bosentan, a dual endothelin A/B receptor antagonist which is similar to anti-PD1 in that it uses an antibody to modify a specific cell receptor, but unlike anti-PD1 the receptor is on the melanoma cell itself, and the hope was that by antagonizing it [blocking it] the cell would die…while anti-PD1 hopes to activate the white cell and bring the immune system to attack the tumor cell.  Anyhow, they tried bosentan alone and combined with dacarbazine but had disappointing results.

4.  One other note on Endothelin B and its expression in melanmoma cells:  In the Polakis paper:  They assayed the amount of cell expression of the receptor and found it to have a range of expression from 1500 to 33000 per cell line.  In their mouse model, they showed efficacy of their ADC for both the low and high end of cell expression.

5.  In my research I found about 70 articles on Endothelin B and melanoma.  Only a few on auristatin, melanoma and endothelin B.  The best article is the one by Asundi….Polakis from Genentech.

6. Take a way:  "It seems that researchers have found a very melanoma specific cell surface receptor, which provides a target using antibodies bonded to a highly potent cell toxin which is rapidly taken in from the cell surface and converted to the active agent inside the cell.  Theoretically, this will allow targeted delivery of extremely cytotoxic agents and in the mouse model produced rapid (i.e. one week…) death of melanoma cells with no recurrence for three months.  The unknowns include: How well this molecule will work in humans?  How much of the toxin will be released to the general circulation? What other cells in the body may have the receptor and therefore may be affected?  Will the molecule penetrate the CNS?  Will there be any side effects from the anti-body?  Also, it is possible for melanoma to develop resistance to this agent via a number of mechanisms.  The actual benefits and side effects using this agent in humans is what you, my friend, are volunteering to answer.  Despite the questions, it does look promising."

It turned out that the process worked for my friend…in that some tumors shrank and other growth was stabilized for about a year, when it happened that tumors began to grow again.  He also experienced some hair loss, fatigue, and neuropathy that was clearly related to "leakage" of the auristatin into the body…not just in the tumor.  For what it's worth here is a post with a summary of an article reporting Phase I/II results of glembatumumab in melanoma patients by Ott, Pavilick, Hamid, Sznol et al….

http://chaoticallypreciselifeloveandmelanoma.blogspot.com/2014/10/another-antibody-drug-conjugate-for.html

Hope that helps those of you interested.  Hang in there, Artie!!!  c

Hey Artie!  Hope you are feeling better????!  Yes, this trial is using glembatumumab vedotin, which links auristatin to the glycoprotein NMB [GPNMB], the Celldex product.  In case folks don't know much about ADC's and what they are….here is something I researched for a friend of mine who participated in the Genentech ADC trial (where auristatin was linked to endothelian B) over a year ago.

1.  ADC (Antibody-Drug Conjugate) = Trojan horse therapy, in which a target antibody is attached via a linker to a cytotoxic agent.  This technique takes a bad news cytotoxin like auristatin, attaches it via a special molecule to a monocolonal antibody that targets antigens preferentially expressed on the surface of targeted cancer cells, in this case – endothelian B, and then sneaks the cytotoxic agent into the targeted tumor cell with no horrible side effects to the rest of the body.  Has been in the works since the 80's. Over that time laboratory researchers have found many more possible monoclonal antibodies to use (and studied which tumors express them the most) and a variety of gradually improving techniques to "link" the chemotherapeutic agent to the antibody.  Improved "linkers" seem to have made it easier to use a variety of antibodies as well as cytotoxic agents and keep the whole little trifecta intact until it reaches its destination. 

2.  Endothelin receptor ETB (Genentech's RG-7636) as well as Glembatumumab vedotin (Celldex's ADC using the receptor GPNMB) are the only two ADC products I can find used against melanoma.  Celldex seems to have withdrawn its product from that line of attack and is focusing its use on breast cancer only at this time.  Though, Sievers paper (Seattle Genentech) reports: "In a phase I/II trial in patients with unresectable late-stage melanoma, CDX-011 (yet another name for Glembatumumab vedotin) showed overall response rates ranging from 14% to 19% depending on dosing frequency and GPNMB expression levels."

3.  Endothelin receptor ETB is apparently expressed on most melanoma tumors (as well as in skin cells in general…and is even in the pathway for their embryonic development).  So much so…that at first folks tried the drug bosentan, a dual endothelin A/B receptor antagonist which is similar to anti-PD1 in that it uses an antibody to modify a specific cell receptor, but unlike anti-PD1 the receptor is on the melanoma cell itself, and the hope was that by antagonizing it [blocking it] the cell would die…while anti-PD1 hopes to activate the white cell and bring the immune system to attack the tumor cell.  Anyhow, they tried bosentan alone and combined with dacarbazine but had disappointing results.

4.  One other note on Endothelin B and its expression in melanmoma cells:  In the Polakis paper:  They assayed the amount of cell expression of the receptor and found it to have a range of expression from 1500 to 33000 per cell line.  In their mouse model, they showed efficacy of their ADC for both the low and high end of cell expression.

5.  In my research I found about 70 articles on Endothelin B and melanoma.  Only a few on auristatin, melanoma and endothelin B.  The best article is the one by Asundi….Polakis from Genentech.

6. Take a way:  "It seems that researchers have found a very melanoma specific cell surface receptor, which provides a target using antibodies bonded to a highly potent cell toxin which is rapidly taken in from the cell surface and converted to the active agent inside the cell.  Theoretically, this will allow targeted delivery of extremely cytotoxic agents and in the mouse model produced rapid (i.e. one week…) death of melanoma cells with no recurrence for three months.  The unknowns include: How well this molecule will work in humans?  How much of the toxin will be released to the general circulation? What other cells in the body may have the receptor and therefore may be affected?  Will the molecule penetrate the CNS?  Will there be any side effects from the anti-body?  Also, it is possible for melanoma to develop resistance to this agent via a number of mechanisms.  The actual benefits and side effects using this agent in humans is what you, my friend, are volunteering to answer.  Despite the questions, it does look promising."

It turned out that the process worked for my friend…in that some tumors shrank and other growth was stabilized for about a year, when it happened that tumors began to grow again.  He also experienced some hair loss, fatigue, and neuropathy that was clearly related to "leakage" of the auristatin into the body…not just in the tumor.  For what it's worth here is a post with a summary of an article reporting Phase I/II results of glembatumumab in melanoma patients by Ott, Pavilick, Hamid, Sznol et al….

http://chaoticallypreciselifeloveandmelanoma.blogspot.com/2014/10/another-antibody-drug-conjugate-for.html

Hope that helps those of you interested.  Hang in there, Artie!!!  c

Hey Artie!  Hope you are feeling better????!  Yes, this trial is using glembatumumab vedotin, which links auristatin to the glycoprotein NMB [GPNMB], the Celldex product.  In case folks don't know much about ADC's and what they are….here is something I researched for a friend of mine who participated in the Genentech ADC trial (where auristatin was linked to endothelian B) over a year ago.

1.  ADC (Antibody-Drug Conjugate) = Trojan horse therapy, in which a target antibody is attached via a linker to a cytotoxic agent.  This technique takes a bad news cytotoxin like auristatin, attaches it via a special molecule to a monocolonal antibody that targets antigens preferentially expressed on the surface of targeted cancer cells, in this case – endothelian B, and then sneaks the cytotoxic agent into the targeted tumor cell with no horrible side effects to the rest of the body.  Has been in the works since the 80's. Over that time laboratory researchers have found many more possible monoclonal antibodies to use (and studied which tumors express them the most) and a variety of gradually improving techniques to "link" the chemotherapeutic agent to the antibody.  Improved "linkers" seem to have made it easier to use a variety of antibodies as well as cytotoxic agents and keep the whole little trifecta intact until it reaches its destination. 

2.  Endothelin receptor ETB (Genentech's RG-7636) as well as Glembatumumab vedotin (Celldex's ADC using the receptor GPNMB) are the only two ADC products I can find used against melanoma.  Celldex seems to have withdrawn its product from that line of attack and is focusing its use on breast cancer only at this time.  Though, Sievers paper (Seattle Genentech) reports: "In a phase I/II trial in patients with unresectable late-stage melanoma, CDX-011 (yet another name for Glembatumumab vedotin) showed overall response rates ranging from 14% to 19% depending on dosing frequency and GPNMB expression levels."

3.  Endothelin receptor ETB is apparently expressed on most melanoma tumors (as well as in skin cells in general…and is even in the pathway for their embryonic development).  So much so…that at first folks tried the drug bosentan, a dual endothelin A/B receptor antagonist which is similar to anti-PD1 in that it uses an antibody to modify a specific cell receptor, but unlike anti-PD1 the receptor is on the melanoma cell itself, and the hope was that by antagonizing it [blocking it] the cell would die…while anti-PD1 hopes to activate the white cell and bring the immune system to attack the tumor cell.  Anyhow, they tried bosentan alone and combined with dacarbazine but had disappointing results.

4.  One other note on Endothelin B and its expression in melanmoma cells:  In the Polakis paper:  They assayed the amount of cell expression of the receptor and found it to have a range of expression from 1500 to 33000 per cell line.  In their mouse model, they showed efficacy of their ADC for both the low and high end of cell expression.

5.  In my research I found about 70 articles on Endothelin B and melanoma.  Only a few on auristatin, melanoma and endothelin B.  The best article is the one by Asundi….Polakis from Genentech.

6. Take a way:  "It seems that researchers have found a very melanoma specific cell surface receptor, which provides a target using antibodies bonded to a highly potent cell toxin which is rapidly taken in from the cell surface and converted to the active agent inside the cell.  Theoretically, this will allow targeted delivery of extremely cytotoxic agents and in the mouse model produced rapid (i.e. one week…) death of melanoma cells with no recurrence for three months.  The unknowns include: How well this molecule will work in humans?  How much of the toxin will be released to the general circulation? What other cells in the body may have the receptor and therefore may be affected?  Will the molecule penetrate the CNS?  Will there be any side effects from the anti-body?  Also, it is possible for melanoma to develop resistance to this agent via a number of mechanisms.  The actual benefits and side effects using this agent in humans is what you, my friend, are volunteering to answer.  Despite the questions, it does look promising."

It turned out that the process worked for my friend…in that some tumors shrank and other growth was stabilized for about a year, when it happened that tumors began to grow again.  He also experienced some hair loss, fatigue, and neuropathy that was clearly related to "leakage" of the auristatin into the body…not just in the tumor.  For what it's worth here is a post with a summary of an article reporting Phase I/II results of glembatumumab in melanoma patients by Ott, Pavilick, Hamid, Sznol et al….

http://chaoticallypreciselifeloveandmelanoma.blogspot.com/2014/10/another-antibody-drug-conjugate-for.html

Hope that helps those of you interested.  Hang in there, Artie!!!  c