XmAb^® Fc Technology

We have created our proprietary XmAb® Fc domains with a wide range of immunological properties. 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. The appropriate XmAb Fc can be selected to improve nearly any antibody for dramatically improved activity or half-life.

Key results on high ADCC XmAb® Fc variants:

• 10-100-fold enhancement in ADCC using human effector cells. We have demonstrated this greatly improved potency in dozens of different antibodies against a wide range of tumor cells.
• Increased binding to both FcγRIIIa and 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.
• Enhanced in vivo efficacy in animals. Multiple mouse xenograft studies and primate blood cell depletion studies show dramatic enhancement of antibody cytotoxic function.
• Enhanced activity in humans. The Phase 1 clinical trial of XmAb2513 in refractory Hodgkin lymphoma showed objective responses from tumors previously resistant to antibody therapy.

Key results on γRIIb XmAb Fc variants:

• More than 400x selective enhancement of binding affinity to FcγRIIb to enable targeting of inhibitory pathways in B cells and other immune cells for autoimmune and allergic disorders
• Ablated binding to FcγRIIIa to eliminate cytotoxic function of the Fc domain, thereby enhancing selectivity and its safety profile
• Efficacious in murine models of rheumatoid arthritis and multiple sclerosis (in XmAb5871 candidate) with minimal depletion of B cells

Key results on Xtend Fc variants:

• Enhanced binding to the receptor FcRn, which results in a two to four-fold increase in in vivo half-life in primates
• No loss of antibody stability, or disruption of binding to FcyR or protein A
• Validated half-life improvements in five antibodies in primates and huFcRn transgenic mice

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

• Selectively or completely eliminated FcγR and complement interaction to completely block effector function for antibodies where immune activation might cause side effects.
• Enhanced interaction with complement proteins to heighten complement dependent cytotoxicity (CDC), another potentially relevant effector mechanism for anti-cancer antibodies.