Therapeutic Product Immunogenicity Community

Hi Community,

If you have been doing IMG analysis for biotherapeutics, you may have worked in some outputs that consider ADA impact on safety, and as per Shakar we look at "infusion reactions and anaphylaxis (6,7) as well as immune complex-mediated diseases..." in addition, depending on the mechanism of action you may consider thromboembolism or others.  In my review of some documents related to cell therapies, I have seen iiNTs (identified by investigators as Neurotoxicity) among the AEs looked into for such outputs.  I don't see how an ADA to CT would have caused NT, can someone help me?  If not, is this just a bad practice started elsewhere that we should stop.

CRS is a bit tricky, b/c the CT itself is associated with it, not the ADA response, but I am hesitant to push back on removing it.

Pls share your thoughts!

------------------------------
Johanna Mora Ph.D.
Bristol-Myers Squibb
Princeton NJ
[email protected]
------------------------------

Hi Johanna,

cross-reactivity to endogenous proteins should be considered as suggested by FDA Guidance on Immunogenicity Assessment for Therapeutic Protein Products (fda.gov)

Unfortunately, often, structurally shared epitops cannot be excluded for ADA.

 
This is the section of Guidance you can refer

5. Cross-Reactivity to Endogenous Proteins

ADA can have severe consequences if it cross-reacts to and inhibits a nonredundant endogenous 
counterpart of the therapeutic protein product or related proteins (Macdougall et al. 2012; Seidl 
et al. 2012). If the endogenous protein is redundant in biological function, inhibition of the 
therapeutic and endogenous proteins may not produce an obvious clinical syndrome until the 
system is stressed, because not all biological functions of an endogenous protein may be known 
or fully characterized (Stanley et al. 1994; Bukhari et al. 2011). Moreover, the long-term 
consequences of such antibodies may not be known. An additional potential consequence of 
cross-reactivity to an endogenous protein results from antibody responses to a therapeutic protein 
product that is a counterpart of an endogenous cell surface receptor or a counterpart of an 
endogenous cytokine that is membrane-expressed. Such antibodies may cross-reactively bind to 
the respective cell surface receptors or proteins, causing cytokine release or other manifestations 
of cellular activation.

Best

Stefano

------------------------------
Stefano Porzio
CMC and Development Director
Enthera Srl
Milano
[[email protected]]

Disclaimer: Opinions expressed are solely my own and do not express the views or opinions of my employer.

[email protected]

Original Message:
Sent: 04-11-2024 14:29
From: Johanna Mora
Subject: ADA and AEs for CT

Hi Community,

If you have been doing IMG analysis for biotherapeutics, you may have worked in some outputs that consider ADA impact on safety, and as per Shakar we look at "infusion reactions and anaphylaxis (6,7) as well as immune complex-mediated diseases..." in addition, depending on the mechanism of action you may consider thromboembolism or others.  In my review of some documents related to cell therapies, I have seen iiNTs (identified by investigators as Neurotoxicity) among the AEs looked into for such outputs.  I don't see how an ADA to CT would have caused NT, can someone help me?  If not, is this just a bad practice started elsewhere that we should stop.

CRS is a bit tricky, b/c the CT itself is associated with it, not the ADA response, but I am hesitant to push back on removing it.

Pls share your thoughts!

------------------------------
Johanna Mora Ph.D.
Bristol-Myers Squibb
Princeton NJ
[email protected]
------------------------------

Yes, of course, thanks for adding this here. The question I am raising asks: is neurotoxicity an expected immunogenicity AE for a cell therapy? If yes, can you explain in which case.

Hi Johanna,

cross-reactivity to endogenous proteins should be considered as suggested by FDA Guidance on Immunogenicity Assessment for Therapeutic Protein Products (fda.gov)

Unfortunately, often, structurally shared epitops cannot be excluded for ADA.

 
This is the section of Guidance you can refer

5. Cross-Reactivity to Endogenous Proteins

ADA can have severe consequences if it cross-reacts to and inhibits a nonredundant endogenous 
counterpart of the therapeutic protein product or related proteins (Macdougall et al. 2012; Seidl 
et al. 2012). If the endogenous protein is redundant in biological function, inhibition of the 
therapeutic and endogenous proteins may not produce an obvious clinical syndrome until the 
system is stressed, because not all biological functions of an endogenous protein may be known 
or fully characterized (Stanley et al. 1994; Bukhari et al. 2011). Moreover, the long-term 
consequences of such antibodies may not be known. An additional potential consequence of 
cross-reactivity to an endogenous protein results from antibody responses to a therapeutic protein 
product that is a counterpart of an endogenous cell surface receptor or a counterpart of an 
endogenous cytokine that is membrane-expressed. Such antibodies may cross-reactively bind to 
the respective cell surface receptors or proteins, causing cytokine release or other manifestations 
of cellular activation.

Best

Stefano

------------------------------
Stefano Porzio
CMC and Development Director
Enthera Srl
Milano
[[email protected]]

Disclaimer: Opinions expressed are solely my own and do not express the views or opinions of my employer.

[email protected]

Original Message:
Sent: 04-11-2024 14:29
From: Johanna Mora
Subject: ADA and AEs for CT

Hi Community,

If you have been doing IMG analysis for biotherapeutics, you may have worked in some outputs that consider ADA impact on safety, and as per Shakar we look at "infusion reactions and anaphylaxis (6,7) as well as immune complex-mediated diseases..." in addition, depending on the mechanism of action you may consider thromboembolism or others.  In my review of some documents related to cell therapies, I have seen iiNTs (identified by investigators as Neurotoxicity) among the AEs looked into for such outputs.  I don't see how an ADA to CT would have caused NT, can someone help me?  If not, is this just a bad practice started elsewhere that we should stop.

CRS is a bit tricky, b/c the CT itself is associated with it, not the ADA response, but I am hesitant to push back on removing it.

Pls share your thoughts!

------------------------------
Johanna Mora Ph.D.
Bristol-Myers Squibb
Princeton NJ
[email protected]
------------------------------