# Presentation: 813305

## Abatacept (hCTLA4-Ig)

**For the Treatment of Rheumatoid Arthritis:**

**Product Attributes and Mechanism of Action**
**Joy Williams, Ph.D.**

**Arthritis Advisory Committee**
**September 6, 2005**

## Abatacept BLA

**(Rolling submission of BLA)**
_**Unit:**_**	****	****	****	****	****	****	****Date of**
**	****	****	****	****	****	****	****submission:****	****	****	****	****	****	****	**
_**	**__**	**__**	**__**	**__**	**__**	**__**	**__**	**_
**Pharmacology and Toxicology reviewable unit****	****	****11/15/04**
**Clinical pharmacology and biopharmaceutics**
**Full clinical reviewable unit****	****	****	****	****12/20/04**
**Chemistry, Manufacturing and Controls (CMC)**
**reviewable unit****	****	****	****	****	****	****3/31/05**

**Abatacept BLA**

**PDUFA action date for BLA 125118 (Abatacept): 12/31/05**

## Review team

_**Regulatory Project manager:**_
**Erik Laughner**
_**Product reviewers:**_
**Joy Williams, chair**
**Elizabeth Shores**
**Susan Kirshner**
**Ennan Guan**
**Edward Max**
**Barbara Rellahan**
_**Clinical reviewers:**_
**Keith Hull – Chair, clinical reviewer**
**Jeffrey Siegel –Team leader**
**Mark Walton-Director**
_**Pharm/Tox:**_
**Anita O'Connor-toxicology reviewer**
**Anil Rajpal-Pharm reviewer**
**Hannan Guan**

_**Statisticians:**_
**Kyung Lee-stat reviewer**
**Boguang Zhen-stat team leader**
_**Facilities reviewer:**_
**Ann deMarco**
_**DSI/BiMo: **_
**Dianne Tesch**
_**DDMAC:**_
**Catherine Gray**
_**DDRE:**_
**Hyon Kwon**

## Abatacept (CTLA4-Ig) homodimer

**Abatacept (CTLA4-Ig) homodimer**

**CTLA-4 domain:**
**Extracellular sequence **
**of human CTLA-4 **

**IgG1 Fc domain:**
**Hinge, CH2 and CH3 regions**
**of human IgG1 Fc sequence**

## Abatacept manufacturing process

**Abatacept for Injection, 250 mg/vial**
**	****sterile, non-pyrogenic lyophile for intravenous **
**	****administration following reconstitution with **
**	****Sterile Water for Injection; supplied with non-siliconized syringe**
**Excipients: maltose monohydrate, sodium phosphate monobasic,**
**Sodium chloride, hydrochloric acid, sodium hydroxide**

_**Abatacept manufacturing process**_

**Abatacept is produced as a secreted protein in**
**large scale culture of Chinese hamster ovary cell line**

**Series of purification/viral clearance steps**

**Antigen presenting cell**

** **

**TCR**

**B7**

**MHC + peptide**

**CD28**

**T cell activation requires signals from TCR**
**	****and costimulatory molecules**

##  T cell

**Antigen presenting cell**

** **

**CTLA4 – a CD28 homologue that**
**binds to B7 with higher affinity than CD28**

**fused to IgG1 Fc**
**to create soluble CTLA4-Ig**

**CTLA4-Ig**

**CTLA4**

**IgG1 Fc**

**B7**

**CTLA4 **
**extracellular domain**

**Antigen presenting cell**

** **

**TCR**

**B7**

**MHC + peptide**

**CD28**

**CTLA4-Ig binds to B7 molecules and inhibits**
**CD28-B7 interactions; suppresses T cell response**

## B7

**B7**

**IDO**

**IDO**

**IDO**

- tryptophan

- kynurenine

**T cell proliferation **
**is inhibited**

- INF-

**Grohmann et al. Nat Immunol. 3:1097-101**
**Mellor et al. JI 171:1652-5**
**Boasso et al. Blood 105: 1574-81**
**Munn et al. JI 172: 4100-10**

## ?

**Additional possible mechanisms of action to consider:**
**Potential functions of the IgG1 Fc portion of abatacept**

**CTLA4**

**IgG1 Fc**

**Binding to**
**Fc receptors**

**Antibody-dependent**
**Cellular cytoxicity (ADCC)**

**Phagocytosis/clearance**
**of opsonized cells**

**?**

**Resulting in elimination of B7-expressing cells**
**and suppression of T cell response**

**B7 expressing**
**cell**

## The paradox: CTLA4-Ig may disrupt critical pathways

**required for maintenance of immune tolerance**

## T regulatory cells are critical components 

**Antigen presenting cell**

**Effector T cell**

**B7-CTLA4**

**T regulatory cells are critical components **
**in the maintenance of peripheral tolerance**
**to tissue-specific self-antigens**

**In both humans and mice, absence of T regulatory cells is associated **
**with aggressive autoimmunity**

**Self-antigen**

## CD28-B7 interactions are essential for both thymic development 

**CD28-B7 interactions are essential for both thymic development **
**of Tregs and for their peripheral homeostasis**

**Decrease in Tregs (CD4+CD25+) cells**
**in lymph nodes** **of** **wildtype mice treated**
**with CTLA4Ig for 10 days**

**Tang et al. *****JI *****171: 3348-52**

**0**

**1**

**2**

**3**

**4**

**% CD4+CD25+ thymocytes**

**wildtype**

**B7 knockout**

**Decreased development of Tregs**
**In the thymus in B7 knockout mice**

**In certain inbred mouse strains, autoimmune disease is exacerbated**
**in the absence of B7 or CD28 due to loss of Tregs**

**Williams et al. *****(not published)***

**Implications for development of fetal immune system during gestation?**

**Antigen presenting cell**

** **

**Activated T cells express CTLA4:**
**CTLA4 transduces a negative signal to T cells and**
**functions to attenuate the immune response**

**TCR**

**B7**

**MHC + peptide**

**CD28**

**CTLA4**

**Antigen presenting cell**

** **

**TCR**

**B7**

**MHC + peptide**

**CD28**

**CTLA4**

**Activated T cells express CTLA4:**
**CTLA4 transduces a negative signal to T cells and**
**functions to attenuate the immune response; **
_**CTLA4-Ig may interfere with this process**_

## Mechanisms of action that may function to ameliorate RA:

**Blocking CD28 costimulation **
**Induction of suppressor antigen-presenting cells (via IDO)**
**Depletion of B7-expressing cells**
_**Mechanisms of action that may exacerbate autoimmunity:**_
**Inhibition of T regulatory (CD4+CD25+) cell maintenance/development**
**Inhibition of endogenous CTLA4 signals**

_**Abatacept (CTLA4-Ig) Mechanism of Action Summary**_