Immunogenicity of mAbs in non-human primates during nonclinical safety assessment

Figures & data

Table 1. Monoclonal antibodies approved in the European Union from 1988 to 2010

INN	Brand name	Approval date
Abciximab	Reopro, CentoRx	1995**
Adalimumab	Humira, Trudexa	2003
Alemtuzumab	MabCampath	2001#
Anti-melanoma antibody fragments*	Tecnemab-K1	1996#
Arcitumomab*	CEA-scan	1996#
Basiliximab	Simulect	1998
Besilesomab*	Scintimun	2010
Bevacizumab	Avastin	2005
Canakinumab	Ilaris	2009
Catumaxomab	Removab	2009
Certolizumab pegol	Cimzia	2007
Cetuximab	Erbitux	2004
Daclizumab	Zenapax	1999#
Denosumab	Prolia	2010
Eculizumab	Soliris	2007
Efalizumab	Raptiva	2004#
Golimumab	Simponi	2009
Ibritumomab tiuxetan	Zevalin	2004
Igovomab*	Indimacis 125	1996#
Infliximab	Remicade	1999
Muromonab	Orthoclone-OKT3	1988**
Natalizumab	Tysabri	2006
Ofatumumab	Arzerra	2010
Omalizumab	Xolair	2005
Palivizumab	Synagis	1999
Panitumumab	Vectibix	2007
Ranibizumab	Lucentis	2007
Rituximab	Mabthera	1998
Sulesomab*	Leukoscan	1997
Tocilizumab	RoActemra	2009
Trastuzumab	Herceptin	2000
Ustekinumab	Stelara	2009
Votumumab*	Humaspect/ Oncospect CR	1998

INN: International nonproprietary name. The infixes that immediately precede -mab indicate the sequence source: u, human; zu, humanized; xi, chimeric; o, mouse; axo, rat/mouse. *Diagnostic/imaging agent. **Country specific approval #Withdrawn from use in the European Union.

Table 2. Incidence and response level, either clearing or neutralizing, of anti-drug antibodies in non-human primates

	Incidence of clearing or neutralizing antibodies in NHP
ADA incidence in NHP	Low	Intermediate	Majority
Low (0–6%)	MAb12	MAb21	MAb30
	MAb14
	MAb16
	MAb17
	MAb25
	MAb29
	MAb31
Intermediate (6–45%)	MAb9	MAb7	MAb20
	MAb26	MAb10	MAb22
	MAb23	MAb24	MAb32
	MAb27		MAb33
High (> 45%)			MAb5
			MAb8
			MAb11
			MAb13
			MAb15
			MAb18
			MAb28

ADA: Anti-drug antibodies. NHP: Non-human primate

Table 3. Incidence and effect of anti-drug antibodies in clinical trials in comparison with non-clinical data

Product	Clinical immunogenicity	ADA response clinical	Non-clinical immunogenicity	ADA response non-clinical
Murine antibodies
MAb1	Marked	Reduced efficacy due to interference	Not available	Not available
MAb2	Negligible	Diminished efficacy and allergic or hypersensitivity reactions	Not available	Not available
MAb3	Negligible	None	Not available	Not available
MAb4	Negligible	Diminished efficacy	Not available	Not available
MAb5	Tolerable	Diminished efficacy possible	High	Clearing
MAb6	Marked	Neutralizing and hypersensitivity	Not available	Not available
MAb7	Tolerable	Unknown	Intermediate	Clearing
MAb8	Marked	Neutralizing	High	None
Chimeric antibodies
MAb9	Tolerable	Allergic or infusion site reactions in few patients	High	Clearing
MAb10	Tolerable	Clearing (in few patients)	Intermediate	Clearing
MAb11	Tolerable	Thrombocytopenia	Intermediate	Thrombocytopenia
MAb12	Tolerable	Unknown	High	Clearing
MAb13	Marked	Neutralizing and hypersensitivity	Low	None
Humanized antibodies
MAb14	Negligible	None	Low	None
MAb15	Negligible	Positive Coombs’ test, Neutralizing antibodies	High	Clearing and neutralizing
MAb16	Negligible	Allergic reaction in 1 patient	Low	Clearing
MAb17	Negligible	None	Low	None
MAb18	Tolerable	Neutralizing	High	Clearing
MAb19	Tolerable	None	Not available	Not available
MAb20	Tolerable	Clearing	Intermediate	Clearing
MAb21	Tolerable	None	Low	Neutralizing and anaphylaxis
MAb22	Negligible	Neutralizing and hypersensitivity	Intermediate	Clearing and neutralizing
MAb23	Tolerable	Clearing	Intermediate	Clearing
MAb24	Tolerable	Possible role in inflammation	Intermediate	Perivascular sheathing, increased exposure
MAb25	Negligible	None	Low	Clearing
Human antibodies
MAb26	Negligible	Unknown	Intermediate	Anemia
MAb27	Tolerable	Neutralizing and binding	Intermediate	Clearing
MAb28	Negligible	None	High	Neutralizing
MAb29	Negligible	None	Low	None
MAb30	Tolerable	Neutralizing	Low	Clearing
MAb31	Negligible	None	Low	None
MAb32	Tolerable	Neutralizing and infusion reactions	Intermediate	Clearing
MAb33	Tolerable	Neutralizing	Intermediate	Clearing

Table 4. Immunogenicity in non-human primates vs. human

			Immunogenicity in NHP
		Not evaluated in NHP	Low	Intermediate	High
Immunogenicity in clinical trials	Low	Murine Murine Murine	Humanized Humanized Humanized Humanized Human Human	Humanized Human	Humanized Human
	Intermediate	Humanized	Humanized Human	Murine Chimeric Chimeric Humanized Humanized Humanized Human Human Human	Murine Chimeric Chimeric Humanized
	High	Murine Murine	Chimeric		Murine