1. Vice President, Cancer Immunology @CytomX Therapeutics, Inc.
CD3-EGFR Probody™ T Cell-engaging Bispecific Induces Tumor Regressions and Increases Safety Window in Preclinical Studies
Bryan A. Irving Ph.D.
Vice President, Cancer Therapeutics, Inc.

2. Presenter Disclosure Information
Bryan A. Irving Ph.D.
The following relationships exist related to this presentation:
CytomX Therapeutics, Inc. (Employee)

3. T-Cell Engaging Bispecifics
T-cell Engaging Bispecific Therapeutics: Highly Potent, but Associated with Safety Liabilities
T-Cell Engaging Bispecifics
T-cell Engaging Bispecific Antibodies (Ab-TCBs)
Bring cytotoxic T cells & cancer cells together
Highly potent but toxic modality – unforgiving for target expression on normal tissue
EGFR/CD3 BiTE in cynomolgus monkeys.1 Kidney and liver toxicity, cytokine storm, inflammatory cell infiltrates in EGFR-expressing organs
EpCAM/CD3 Catumaxomab: drug-related fatal hepatic failure at 10ug dose (trial terminated).2
Challenging to use for solid tumors
Target Cell
T Cell
Nature Biotechnology 23, (2005)
1Lutterbuese et al., (2010) PNAS 107: 12605
2Mau-Sorensen, M et al. Cancer Chemother Pharmacol (2015) 75:

4. Probody™ Therapeutics are Designed to be Activated in the Tumor Microenvironment
ANTI-CANCER
ANTIBODY
PROTEASE-CLEAVABLE LINKER
MASKING PEPTIDE
PROTEASES
Well-established that upregulated protease activity is a hallmark of most if not all cancers, while proteases are tightly controlled in normal tissues. The Probody platform aims to take advantage of this distinction by engineering a protease-activatable substrate into a recombinant antibody
CytomX Probody linkers are designed to be cleaved by multiple proteases for utility across tumor types
PROBODY is a trademark of CytomX Therapeutics, Inc. All other brands and trademarks referenced herein are the property of their respective owners.

5. EGFR-dependent Cytotoxicity
EGFR/CD3 Probody TCB Attenuates Cytotoxicity >1000x in vitro that is Fully Recovered by Protease Treatment
Probody Bispecific (Pb-TCB)
Protease-cleaved, Recovered potency
>1000x
EGFR-dependent Cytotoxicity
Fc effector mutant(s)
a-CD3 scFvs
a-EGFR
Protease cleavable linker
mask

6. EGFR/CD3 Probody TCB Induces Regressions of Established HT-29 Tumors in T-Cell Engrafted NSG mice
Ab-TCB
Pb-TCB
Dose-dependent activity
Ab-TCB & Pb-TCBs demonstrate comparable anti-tumor

7. Concentration TCB in Plasma
Probody TCBs Protect from Cytokine Release and Organ Toxicity While Extending PK in Cynomolgus Monkeys
IL-6
~33x
Concentration TCB in Plasma
Pb-TCB >300 Fold Higher Exposure Than Toxic Ab-TCB
>300X
Dose (mg/kg)
~33x
AST
Dose (mg/kg)

8. EGFR Probody TCBs Expand Therapeutic Window in Preclinical Studies
Efficacy: Potent tumor activity despite strong masking
Attenuates target binding and T cell cytotoxicity >1000-fold in vitro under protease-deficient conditions
Is highly effective in vivo, eliminating established tumors
Safety: Reduced cytokine and organ toxicities despite high exposure
Probody TCB MTDs are >30 times that of the corresponding antibody TCB
Tolerated Probody TCB serum concentrations are >300 times than for toxic antibody TCB dose
Probody technology has the potential to protect normal tissues and expand utility for bispecifics, especially for solid tumors

9. Acknowledgements Sherry L. La Porte Daniel R. Hostetter Laurie Wong
O. Jennifer Razo
Linnea Diep
Clayton W. White
Jennifer H. Richardson
W. Michael Kavanaugh
CytomX Therapeutics, Inc.