Friday, October 25, 2013

Antibody Engineering Poster: Azymetric Bispecific CD3-CD19 T-cell Engaging Antibodies For Treatment of Cancers

Leading up to the Antibody Engineering Event, we'll be sharing the posters that will be featured in the Exhibit Hall.  Antibody Engineering & Therapeutics will take place December 8-12, 2013 in Huntington Beach, California.  For more information the program, download the agenda.  If you'd like to join us, as a reader of this blog, when you register to join us and mention code XD13172BLOGJP, you'll save 20% off the standard rate!

Poster: Azymetric Bispecific CD3-CD19 T-cell Engaging Antibodies For Treatment of Cancers

Presenter: Gordon Ng, Zymeworks

About the Poster: Blinatumomab (AMG330) is a CD3-CD19 single-chain Bispecific T-Cell Engaging (BiTE) Antibody that has shown exciting Phase 2 clinical efficacy in ALL. Blinatumomab has provided important clinical validation of the T-cell engaging and target B cell killing mechanism of action. However, single-chain bispecific antibodies can lead to poor biochemical properties and manufacturing issues, and Blinatumomab treatment has been associated with cytokine flares, neurological adverse effects, and a short half-life of several hours post IV dosing. We have reported that Azymetric® engineering of human IgG1 CH2 and CH3 domains provides a rational structure-based approach to the design of novel bispecific IgG antibodies with tailored effector functions and enhanced Fc heterodimer formation. Azymetric® bispecific antibodies may represent a new class of T-cell engaging antibodies with equal if not better drug-like properties compared to single-chain bispecific formats. Side-by-side comparison with CD3-CD19 BiTE (generated based on literature data) has shown that Azymetric® CD3-CD19 bispecific IgG antibodies can independently bind CD3+ T cells and CD19+ B cells, and bridge T-B cells. Similar specificity of T and B cell binding was obtained with an Azymetric® CD3-CD20 antibody. Azymetric® CD3-CD19 antibodies can redirect both IL-2 stimulated and unstimulated human PBMC and isolated T cells for lysis of human B lymphoma Raji cells or autologous B cells. The in vitro potency and efficacy is comparable to CD3-CD19 Bite. Azymetric® CD3-CD19 antibody mediated B cell cytotoxicity is partially blocked by IgG suggesting that cytotoxic activity owed to linking T and B cells and T cells becoming activated. The Fc-independent mechanism was confirmed in cytotoxicity studies using purified T and B cells and extended with CD3-CD19 Azymetric® antibodies with Fc heterodimers lacking FcγR binding. The CD3-CD19 Azymetric® antibody was more selective than CD3-CD19 BiTE by sparing autologous T cells. At maximal concentrations that elicited T-cell engagement and redirected B cell killing, CD3-CD19 Azymetric® antibodies with wild-type or Fc knocked-out effector activity had no significant effect on PBMC proliferation nor induced cytokine release. At 100-fold higher concentrations, the Azymetric® CD3-CD19 antibody with the wild-type heterodimer Fc did elicit PBMC proliferation and cytokine release. The Azymetric® Fc can mediate ADCC and ADCC may be a feature of a molecule’s clinical efficacy as claimed for the trifunctional CD3-EpCAM bispecific IgG antibody Catumaxomab. Azymetric® CD3-CD19 bispecific IgG antibodies expressed in CHO cells had significantly higher yields compared to CD3-CD19 BiTE, and can be readily purified in a stable form using Protein A and other conventional process resins. Quantitative LCMS of the purified antibody showed >95% purity of the Azymetric® heterodimer antibody with no detection of CD3 or CD19 homodimers. Mouse PK studies showed Azymetric® antibodies exhibit typical IgG1 like PK parameters. Taken together, these studies suggest that the Azymetric® heterodimeric Fc antibody format shows appropriate pharmacological properties, and manufacturability characteristics suitable for developing BiTE therapeutic antibodies.

Do you have new research to share with your industry colleagues?  Your poster can be featured in the Antibody Engineering Exhibit hall as well!  <a href="" target="_blank">Find out how here</a>. &nbsp;The deadline for poster submissions is November 1.

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1 comment :

Unknown said...

I found that you have so much information about antibodies.....Please tell me what is the difference between antibody sigma and monoclonal antibodies ?

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