June, 2015

Antibody Therapeutics: Trends & Future Directions
2

Biologic Therapeutics

Major industry focus and the 

focus of this presentation

Antibodies Gene 

therapy Vaccines Replacement

therapy 

Cell

therapy

Infectious 

disease, 

cancer

Insulin,

enzymes, 

coagulation 

factors

Single gene 

defects,

therapeutics

Modified 

lymphocytes 

(chimeric antigen 

receptors), stem 

cells, chondrocytes 
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FDA Approval of Antibodies and Antibody-Like Molecules

49 molecules approved from 1986 to December 2014

First 16 molecules:

16 years

Disease target:

Autoimmune = 38%

Cancer = 31%

Other = 31%

2nd 16 molecules:

7.5 years

Disease target:

Autoimmune = 50%

Cancer = 31%

Other = 19%

Last 17 molecules:

3.5 years

Disease target:

Cancer = 53%

Other = 35%

Autoimmune = 12%

0

1

2

3

4

5

6

7

8

9
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Evolution of Antibody Therapeutics

1986 2000 2002 2012

Monoclonal

antibody

OKT3 Mylotarg

Antibodydrug conj.

Zevalin

Radioconjugate

Gazyva

ADCC 

enhanced

2014

Blincyto

Bispecific

Murine Chimeric Humanized Human

1986 1994 1997 2002
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Antibody Drug Conjugates (ADCs)

Next generation molecules encompass:

- Homogenous, site-specific conjugation

- More potent toxins; resistance to drug efflux

pumps, cell-cycle independent MOA

Industry leaders:

Adcetris

Approved – 2011

Hodgkin Lymphoma

Kadcyla

Approved – 2013

HER2+ Breast Cancer
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Fc-Optimized Antibodies

Musolino, et al., JCO 2008

ADCC-enhanced

Weiner - Nature Reviews, 2015
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Fc-Modified Antibodies

Reduced Fc activity - several checkpoint mAbs incorporate this strategy

(1) Fc-mutation (Ala-Ala) or (2) Use of different isotype (IgG4)

e.g. MPDL3280A (anti-PDL-1) e.g. nivolumab (anti-PD-1)

Huge investment in this drug class:

Total 

Trials 

(inc. PI-led)

Active Industry Sponsored Trials

Phase 

3

Phase

2

Phase 

1 Total Single 

agent 

Combo 

studies

% 

Combo

PD-1

BMS Nivolumab 64 13 16 7 36 16 20 56%

Merck Keytruda 61 6 12 8 26 15 11 42%

PD-L1

MedImmune MEDI4736 26 1 10 10 21 6 15 71%

Genentech MPDL3280A 19 2 6 10 18 7 11 61%

Pfizer/Merck Kgaa MSB0010718C 3 0 2 1 3 3 0 0%

Total 173 22 46 36 104 47 57 55%
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Bispecific Molecules: Easily Configured for Range of Modalities
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Bispecific Molecules: Redirected T Cell Killing

Next generation molecules are under clinical investigation

- Increased potency and improved patient convenience

- Redirected NK cell killing is also being investigated

- Both solid tumors and hematological malignancies targeted

Blincyto – first FDA-approved bispecific (December 2014)

- Complete response rate > 40% in R/R ALL
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Examples of Bispecific Molecules in Clinical Trials

Targeting 2 soluble ligands Dual-targeting a single cell

CD79B CD32B

Inhibition of B cell 

activation signal

Emerging industry effort to dual-target checkpoint inhibitors

e.g. VEGF-A x ANG-2 (Phase 3) e.g. CD79B x CD32B (Phase 1)
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Trends and Future Directions: Next 5-10 Years

• Increased effort to more specifically target tumors, particularly in 

the context of potent empowered antibodies

- Dual targeting of tumor antigens e.g. bispecific ADCs

- Novel strategies e.g. masked antibodies

• Increased focus on combination therapy

- Antibody-antibody combinations 

- Combinations across different modalities e.g. vaccines or chimeric 

antigen receptors (CARs) with checkpoint inhibitor antibodies

- Novel-novel combinations will need to overcome economic hurdles

• Technological breakthroughs generated by cancer-focused 

research should start to filter through to other disease areas

- Infectious disease; redirected T cell killing and cell therapy