Xencor

XmAb™ Fc Technology

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Our proprietary XmAb™ Fc domains are a modular and reusable suite of antibody components we developed by identifying and engineering antibody Fc regions for select amino acid changes. These Fcs have been shown to improve the potency of a number of antibodies against tumor cells by more than 100-fold. Because we have created XmAb™ Fc domains with a wide range of immunological properties, the appropriate one can be selected to improve nearly any antibody. This immune-mediated cell killing is called Antibody-Dependent Cellular Cytotoxicity (ADCC). In addition to greatly heightened cytotoxic activity, we have Fc variants that eliminate immune cell recruitment or that selectively engage immune receptors. Nearly 2,000 different Fc variants have been designed and tested, and their compositions of matter have been protected with numerous patent filings. We are able to mine this large repertoire of proprietary Fc compositions of matter to continue to load our pipeline as well as facilitate multiple partnerships.

Key results on enhanced potency XmAb™ Fc variants:

• Enhanced Fc receptor affinity for greater cytotoxic potency. We have generated and experimentally validated several XmAb™ Fc sequences that demonstrated over 100-fold tighter binding to the activating receptor FcγRIIIa, some of the largest improvements ever reported.
• Over 100-fold enhancement in ADCC using human effector cells. We have demonstrated this greatly improved potency in over 12 different antibodies against a number of target cells, including non-Hodgkin's and Hodgkin's lymphoma, and breast, colorectal, liver, ovarian and prostate cancers.
• Increased binding to FcγRIIa, resulting in heightened cytotoxicity from multiple immune effector cells, including macrophages and neutrophils, both of which are important in combating infectious pathogens and tumors.
• Enabled ADCC killing against cell lines expressing low levels of antigen. We have enabled ADCC killing against cells that previously showed little or no demonstrable cytotoxicity using an antibody with a native (unmodified) Fc region.
• Enhanced in vivo efficacy in animals. A study in cynomolgus monkeys showed that the effective dose required to clear circulating B cells was approximately 50-fold less for a selected XmAb™ Fc Rituxan® variant relative to wild-type Rituxan®.

In addition to cellular cytotoxic activities, we have modulated other effector functions with our Fc variants.

• Enhanced binding to the receptor FcRn, which results in a two to four-fold increase in in vivo half-life.
• Selectively or completely eliminated FcγR and complement interaction to completely block effector function for antibodies where immune activation might cause side effects.
• Selectively bind FcγRIIb to enable targeting of inhibitory pathways in B cells and mast cells for autoimmune and allergic disorders.
• Enhanced interaction with complement proteins to heighten complement dependent cytotoxicity (CDC), another potentially relevant effector mechanism for anti-cancer antibodies.