Bispecific Fusion Antibodies. Exhibit 100% Breadth and Picomolar Potency. Craig Pace, PhD

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1 The Aaron Diamond AIDS Research Center Affiliate of The Rockefeller University Bispecific Fusion Antibodies PG9 Ibalizumab & VRC Ibalizumab Exhibit % Breadth and Picomolar Potency Craig Pace, PhD AIDS Vaccine Conference, Bangkok, Thailand, September 4 th,

2 Studies indicate passive administration of neutralizing antibodies can prevent and treat HIV infection.

3 Breadth and potency of broadly neutralizing mabs Breadth (%) st generation 2 nd generation (select) Engineered ( g/ml) IC b2 2G2 2F5 4E PGT 2 VRC-PG4 PGT 45 PG6 VRC-CH3 PG9 VRC 3BNC7 VRC-iMab Error bars indicate median ± interquartile range of all viruses

4 Breadth and potency of broadly neutralizing mabs Breadth (%) st generation 2 nd generation (select) ( g/ml) IC b2 2G2 2F5 4E PGT 2 VRC-PG4 PGT 45 PG6 VRC-CH3 PG9 VRC 3BNC7 VRC-iMab Error bars indicate median ± interquartile range of all viruses

5 Ibalizumab gp core bridging sheet V3 loop CD4 Humanized anti CD4 domain 2 mab Safe and effective in vivo Currently undergoing Phase IIb trial Freeman et al,

6 Antiviral activity of against 8 HIV viruses Neutra alization/saturatio on (%) zation/saturat tion (%) Neutraliz on/saturation (% Neutralizati - sensitive viruses.... Ibalizumab concentration ( g/ml) )resistant viruses Ibalizumab concentration ( g/ml) Ibalizumab concentration (µg/ml) Maximum per cent inhibition (M MPI)..... percent of viruses (descending MPI) IC5 5 (µg/ml) Colored lines indicate neutralization curves; black lines indicate Ab binding curves

7 Antiviral activity of against 8 HIV viruses Neutra alization/saturatio on (%) zation/saturat tion (%) Neutraliz on/saturation (% Neutralizati - sensitive viruses.... Ibalizumab concentration ( g/ml) )resistant viruses Ibalizumab concentration ( g/ml) Ibalizumab concentration (µg/ml) Maximum per cent inhibition (M MPI) percent of viruses (descending MPI) IC5 5 (µg/ml) Colored lines indicate neutralization curves; black lines indicate Ab binding curves

8 Antiviral activity of against 8 HIV viruses Neutra alization/saturatio on (%) zation/saturat tion (%) Neutraliz on/saturation (% Neutralizati - sensitive viruses.... Ibalizumab concentration ( g/ml) )resistant viruses Ibalizumab concentration ( g/ml) Ibalizumab concentration (µg/ml) Maximum per cent inhibition (M MPI) percent of viruses (descending MPI) IC5 5 (µg/ml) Colored lines indicate neutralization curves; black lines indicate Ab binding curves

9 Bispecific concentrates bnabs at the site of viral entry V H V L V L V H V H V H V L V L C H C H C L C L C H2 C H2 C H3 C H3 PG9 imab or VRC imab

10 PG9 imab and VRC imab exhibit exceptional potency and breadth VRC-iMab Maximum per cent inhibition (M MPI).... IC5 5 (µg/ml). percent of viruses (descending MPI) CAVD reference panel of 8 HIV Env pseudoviruses representing diversity by clade, ld geography, tropism and stage of infection

11 PG9 imab and VRC imab exhibit exceptional potency and breadth VRC-iMab Maximum per cent inhibition (M MPI).... IC5 5 (µg/ml) percent of viruses (descending MPI) CAVD reference panel of 8 HIV Env pseudoviruses representing diversity by clade, ld geography, tropism and stage of infection

12 PG9 imab and VRC imab exhibit exceptional potency and breadth Maximum per cent inhibition (M MPI) 95 VRC-iMab.... IC5 5 (µg/ml) percent of viruses (descending MPI) CAVD reference panel of 8 HIV Env pseudoviruses representing diversity by clade, ld geography, tropism and stage of infection

13 Breadth and potency of broadly neutralizing mabs Breadth (%) st generation 2 nd generation (select) ( g/ml) IC b2 2G2 2F5 4E PGT 2 VRC-PG4 PGT 45 PG6 VRC-CH3 PG9 VRC 3BNC7 VRC-iMab Error bars indicate median ± interquartile range of all viruses

14 Breadth and potency of broadly neutralizing mabs Breadth (%) st generation Engineered 2 nd generation (select) ( g/ml) IC b2 2G2 2F5 4E PGT 2 VRC-PG4 PGT 45 PG6 VRC-CH3 PG9 VRC 3BNC7 VRC-iMab Error bars indicate median ± interquartile range of all viruses

15 Breadth and potency of broadly neutralizing mabs Breadth (%) st generation 2 nd generation (select) Engineered ( g/ml) IC b2 2G2 2F5 4E PGT 2 VRC-PG4 PGT 45 PG6 VRC-CH3 PG9 VRC 3BNC7 VRC-iMab Error bars indicate median ± interquartile range of all viruses

16 PG9 imab achieves greater viral coverage than the sum of 26 mabs overage (%) Viral co mab concentration (µg/ml) µg/ml Theoretical maximum* PG9 imab VRC imab PGT2 or % 99% 97% 63%.2 62% 82% 4% % Adapted from Walker et al,

17 Mechanism of the enhanced potency of PG9 imab

18 Co administration of and PG9 IgG yields only additive effects G9 6_ PG9 imab + PG9 % In nhibition -... Ab con (nm) G Ab con (nm) TRO.c imab PG9 imab + PG Ab con (nm) Ab concentration (nm) Ab con (nm)

19 Enhanced potency of PG9 imab is entirely dependent on CD4 binding activity % In nhibition G9 PG9 P-i Pi(M2) P-i(M2) imab -... Ab con (nm) G - Q Ab con (nm) TRO.c PG9 PG9 P-i P-i(M2) imab imab PG9 PG9- imab P-i P-i(M2) irhfc Ab con (nm) Ab concentration (nm) Ab con (nm)

20 Summary PG9 imab and VRC imab each neutralize % of HIV viruses tested PG9 imabexhibitsexceptional exceptional potency median IC5 5 ng/ml (24 pm) median IC99 ng/ml (385 pm) The enhanced potency of PG9 imab is entirely CD4 anchoring dependent.

21 Acknowledgements ADARC David Ho Ruijiang Song David Franco Yaoxing Huang Neal Padte Beth Israel Deaconess Michael Seaman IAVI/TSRI Dennis Burton Wayne Koff