TAHHP Antibody Summaries

The Therapeutic Antibody Human Homology Project is my attempt to group therapeutic monoclonal antibodies which have been used in human therapeutic trials according to their homologies with human germline immunoglobulin genes. My hope is that this will make it easier to identify whether there is any correlation between the efficacy of these antibodies (particularly regarding immune responses to the antibody) and the sequences of the variable regions.

Homologies for Antibody Heavy Chain V regions

Antibody	Specificity	V-region	Homologous VH	JH	Length	Matches	Homology
anti-CD20	CD20	Mouse	DP-7_21-2-	JH2	121	81	0.669
Campath-1H	CD52	Humanised	DP-71_3D197D-	JH4D	121	86	0.710
Campath-1G	CD52	Rat	DP-34_DA-10	JH4D	121	85	0.702
anti-Tac	CD25	Mouse	HV1F10T	JH4D	116	84	0.724
FOG-1	RhD	Human	V4-34	JH6A	124	100	0.807
anti-TNFa	TNF-alpha	Mouse	VI-4-IB	JH3B	117	84	0.718

Homologies for Antibody Light Chain V regions

Antibody	Specificity	V-region	Homologous VK	JK	Length	Matches	Homology
anti-CD20	CD20	Mouse	VG_38K-	JK2	106	71	0.670
Campath-1H	CD52	Humanised	DPK1_018-	JK1	107	93	0.869
Campath-1G	CD52	Rat	DPK9_012-	JK2	107	81	0.757
anti-Tac	CD25	Mouse	DPK26_A26-	JK4	106	72	0.679
FOG-1	RhD	Human	A30_SG3	JK2	107	101	0.944
anti-TNFa	TNF-alpha	Mouse	L10a	JK4	107	71	0.664

Overall Homologies for Antibody Heavy and Light Chain V regions

Antibody	Specificity	V-regions	Length	Matches	Homology	Reference
anti-CD20	CD20	Mouse	227	152	0.670	Liu et al 1987
Campath-1H	CD52	Humanised	228	179	0.785	Riechmann et al 1987
Campath-1G	CD52	Rat	228	166	0.728	Riechmann et al 1987
anti-Tac	CD25	Mouse	222	156	0.703	Queen et al 1989
FOG-1	RhD	Human	231	201	0.870	Bye et al 1992
anti-TNFa	TNF-alpha	Mouse	224	155	0.692	Doering et al 1994

What's going on?

As can be seen from the small number of sequences of therapeutic antibodies so far run against V-base there are only relatively small improvements in overall homology with human germline genes as a result of humanisation. The humanised and mouse sequences compare very favourably with a human antibody FOG-1 which was isolated from an immune donor.

Why is this? First it is important to remember that V-base containing the sequences of all known immunoglobulin germline genes has only been available recently [Cook & Tomlinson 1995, Tomlinson et al 1995, Williams et al 1996]. Until then the sequences used as acceptors for the humanisation process were derived from databases such as Kabat [Johnson & Wu 2000] containing a mixture of sequences including rearranged genes and myeloma proteins. For example the rat antibody Campath-1G was humanised by CDR grafting to the myeloma sequences NEW and REI to give the humanised form Campath-1H [Riechmann et al 1988]. What is now clear from the above analysis is that original Campath-1G rat sequences had human homologues in which the homology extended througout the whole sequence including the CDR1 and CDR2 regions withn the VH segment. In contrast the CDR grafting process onto NEW has in fact generated sequences for which there is no good human germline gene homologous for the whole segment i.e. the CDR regions are no longer characteristic of the chosen FRs

References

Bye J.M., Carter C., Cui Y., Gorick B.D., Songsivilai S., Winter G., Hughes-Jones N.C., Marks J.D. (1992) Germline variable region gene segment derivation of human monoclonal anti-Rh(D) antibodies. Evidence for affinity maturation by somatic hypermutation and repertoire shift. J. Clin. Invest. 90:2481-2490
Cook, G.P and Tomlinson, I.M. (1995) The human immunoglobulin VH repertoire. Immunol. Today 16, 237-242
Doering, E., Stigler, R., Gruetz G., Von Baehr, R., Schneider-Mergener, J. (1994) Identification and characterization of a TNFalpha antagonist derived from a monoclonal antibody. Mol. Immunol. 31:1059-1067
Johnson, G. and Wu, T.T. (2000) Kabat Database and its applications: 30 years after the first variability plot. Nucleic Acids Research, 28, 214-218
Liu A.Y., Robinson R.R., Murray E.D.JR., Ledbetter J.A., Hellstroem I., Hellstroem K.E. (1987) Production of a mouse-human chimeric monoclonal antibody to CD20 with potent Fc-dependent biologic activity." J. Immunol. 139:3521-3526
Queen, C. et al (1989) A humanized antibody that binds to the interleukin 2 receptor. Proc. Natl. Acad. Sci. USA 86, 10029-10033
Riechmann, L. et al (1988) Reshaping human antibodies for therapy. Nature 332, 323-327
Williams, S.C. et al (1996) Sequence and evolution of the human germline V lambda repertoire. J. Mol. Biol. 264, 220-232
Tomlinson, I.M. et al (1995) The structural repertoire of the human V kappa domain. EMBO J. 14, 4628-4638

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Mike Clark
"An antibody engineer who also enjoys the mountains."
mrc7@cam.ac.uk
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