Anti-CD38 anti-cd3 bispecific antibody in multiple myeloma

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1 Anti-CD38 anti-cd3 bispecific antibody in multiple myeloma David E. Szymkowski Senior Director, Biotherapeutics Proteins by Design

2 1960s s s... Where are the bispecific antibody drugs? J Exp. Med 1964; 119(1)151 "It would be advantageous in the case of certain diseases to be able to focus a strong T-cell response at a chosen target, for example, in treating cancer or infections that have escaped the normal host response." Staerz, Kanagawa & Bevan, Nature 1985 Amgen, 2014

3 A better format for T cell-recruiting bispecifics Anti tumor antigen Anti CD3 Advantages of Fc-containing bispecific antibodies: Long duration of action mediated by FcRn No implanted port/continuous pump infusions Standard iv infusion or even sc injection likely Undesirable Fc effector functions removed Anti tumor antigen Anti CD3 Humanized & crossreacts with nonhuman primates Lower risk of immunogenicity Enables preclinical safety & efficacy studies Fc domain allows industry-standard manufacturing "Plug & Play" with existing antibodies Any antibody can be paired with anti-cd3 domain No new R&D for every bispecific "Fab - scfv - Fc" format BiTE, DART & other non-fc formats

4 Redirected T Cell-mediated Cytotoxicity (RTCC) by full-length bispecifics αcd3 % RTCC In vitro killing by T cells Myeloma cell line Long IgG1-like half-life in mice Serum Conc ( g/ml) t 1/2 = 7.6 days αher2 αcd3 % RTCC Breast cancer cell line Serum Conc ( g/ml) t 1/2 = 6.2 days αcd19 αcd3 Lymphoma cell line Serum Conc ( g/ml) t 1/2 = 6 days Vs. 75 minute T½ of BiTE (blinatumomab) in humans

5 RTCC of B cell line by αcd19 Fc format vs. BiTE bispecifics BiTE format (αcd19 ) XENP11343 (lot 1) XENP11343 (lot 2) Fc-containing bispecifics XENP11338 XENP11355 XENP11356 αcd19 Log [antibody (ng/ml)] Fluorescent LDH RTCC assay (24hr). 10k Raji cells + 400k T cells

6 Extensive & prolonged B cell killing in cynos by single dose of αcd19 Fc bispecific % CD20 + B cells in lymphocyte fraction 10 BiTE format % CD20 + B cells XENP11355 (0.03 mg/kg) XENP11355 (0.3 mg/kg) XENP11355 (3 mg/kg) XENP11343 (0.01 mg/kg) 0.03 mpk Fc-containing format 0.3 mpk 3 mpk αcd Time (days) Single IV bolus in cynomolgus monkeys (n=3/group)

7 CD38 in multiple myeloma "...everyone agreed that the anti-cd38 compounds are both the most exciting and most likely to add a new mechanism of action to our current combination approaches." (ASH2013 blog of Brian G.M. Durie, Cedars-Sinai) Anti-CD38 antibodies in clinical trials (with native IgG1 Fc) SAR NCT , NCT ImmunoGen/Sanofi Daratumumab NCT574288, NCT Genmab/J&J MOR03087 NCT Morphosys/Celgene

8 Killing of human myeloma line by bispecifics vs monospecific mabs Purified T cells PBMCs 60 % Killing of target cell % Killing of target cell 10 MOR Log [antibody (ng/ml)] αrsv controls Daratumumab Purified T cells: 2x x10 4 RPMI8226, 24 hr PBMCs: RPMI8226, 24 hr

9 Serial killing of target cells via 20:1, 10:1 Day 1 Day 2 1:1 1:2 1:4 20:1, 10:1 1:1 1:2 1:4 80-fold range of Effector : Target cell ratio (T cell : RPMI8228) Day 3 1:1 20:1, 10:1, 1:2 1:4 Bispecific stimulates serial T cell killing of target cells even at low E:T ratios

10 CD38 + CD138 + cell depletion in MM PMBC by bispecific antibodies CD38+ CD138+ cell number Multiple myeloma PBMC + anti-cd3 x CD38 (1 μg/ml) for 24 hr

11 Human plasma cell killing by in hupbmc-engrafted SCID mice Leukapheresis & hupbmc-scid engraftment Dose mab Dose mab TTd vaccination Determine human IgG, IgM, IgE, αttd α-asgm1 to deplete mouse NK cells days Antibody Target Format Rationale XmAb13694 Anti-CD38 Anti-CD3 bispecific High affinity for CD38 Daratumumab Anti-CD38 Monospecific Target cell (IgG1) control XENP13245 Anti-RSV Anti-CD3 bispecific T cell control

12 Suppression of human anti-tetanus in hupbmc- SCIDs by vs daratumumab (Dara) αrsv PBS mg/kg XmAb13694 Dara αrsv Day 0: PBMC engraftment (n=10/group). Days 7 &15: Dose Ab. Day 8: Tetanus. Day 21: Assess human Igs BLQ < 2 miu/ml

13 Human IgG & IgM depletion in hupbmc-scids Human IgG2 Human IgM (Dara) αrsv (Dara) αrsv PBS mg/kg PBS XmAb13694 Dara αrsv XmAb13694 Dara αrsv BLQ < 1 μg/ml BLQ < 30 ng/ml Day 0: PBMC engraftment (n=10/group). Days 7 &15: Dose Ab. Day 8: Tetanus. Day 21: Assess human Igs

14 Prospects for anti-cd38 antibodies & bispecifics Daratumumab SAR MOR03087 Monospecific antibodies Anti CD38 Bispecific scaffolds w/o Fc domain Anti CD38 BiTEs, DARTs Tandabs, etc. Anti CD3 Bispecific antibodies w/fc domain Anti CD38 Anti CD3 XmAb ) Bispecific T cell-mediated killing may be more potent & effective than mabs. 2) Long half-life of Fc may offer superior dosing regimen vs. existing T cell bispecifics. Blinatumomab: A historical perspective. Nagorsen, Kufer, Baeuerle, Bargou. Pharmacol & Therapeutics "All three short-term infusion trials were terminated early based on assessments of the overall benefit/risk profile. Neurologic AEs, cytokine release syndrome, and infections were observed in patients in the absence of objective clinical responses or robust signs of biological activity such as a sustained reduction of peripheral CD19+ B cells"

15 Acknowledgments