Can cancer brain metastases be treated using

humanized monoclonal antibodies: a pilot pharmacological study

Guilhem BOUSQUET, Anne JANIN

University Paris VII, UMR_S1165

Brain metastases

• Most frequent brain tumors

• 15-40% patients with metastatic cancer –

even more in autopsy series

• Lung, breast, melanoma

• Low median survival

• Increased incidence in the last 10 years

because…

• better control of localisations outside

the central nervous system

• an inadequate transfer through

the blood brain barrier (BBB)

of most chemotherapeutic agents

…of

Blood Brain Barrier

• Tight continuous junctions

• Prevent the free paracellular diffusion

of water-soluble molecules, >150Da

• Murin models: BBB permeable,

but concentrations pharmacologically inactive

Reese, J Cell Biol 1967Wilhelm, Acta Neurobiol Exp 2011Lockman, Clin Cancer Res 2010

Brain metastases and breast cancer

• 5-15%

• Risk factors:

– Young age

– Black women

– Triple negative and HER2-overexpressed

phenotypes

• Median survival: less than 12 months

HER2 and brain metastases 

• After treatments for localized breast cancer

– Meta-analysis on 6738 patients

– Trastuzumab-based chemotherapy

– RR of brain metastases=1.57

• In case of metastatic disease

– Incidence of brain metastases: 20-48%

Leyland-Jones, JCO 2009Bria, Breast Cancer Res Treat 2008

Chemocurability …

… with anti-HER2 antibodies

Brain metastases are challenging our daily practice

From Swain SM et al. N Engl J Med 2015.

Trastuzumab

• After intra-veinous injection – Very low passage from blood to brain– Ratio 300/1 à 1000/1 – 148 kDa

• After intra-thecal injection – Proof of concept in case of carcinomatous

meningitidis– Empirical doses ranging from 25 to 100mg

Pestalozzi, 2000Stemmler, 2006Mir, 2008

Trastuzumab

• After intra-veinous injection – Very low passage from blood to brain– Ratio 300/1 à 1000/1 – 148 kDa

• After intra-thecal injection – Proof of concept in case of carcinomatous

meningitidis– Empirical doses ranging from 25 to 100mg

Pestalozzi, 2000Stemmler, 2006Mir, 2008

• 36-year-old woman• HER2-overexpressing breast cancer• Liver metastases, complete response under

trastuzumab treatment• Resistant brain metastases

• Ventricular and lumbar reservoirs • Intra-thecal injections of trastuzumab

A sequential pharmacological pilot study

Overexpression of HER2

Cerebellous metastasis

Treatments

Sampling

Pharmacology

Pre-C1 Pre-C7 Post-C10

Bousquet G, Darrouzain F, Janin A. J Clin Oncol 2015

A rapid clearance of the drug

from the cerebro-spinal fluid

• Cynomolgus monkeys

– Trastuzumab, lumbar catheter,

– 6 males and 6 females received weekly intrathecal

injections.

– A rapid decrease in CSF concentration of trastuzumab.

– A long terminal half-life of about 10 hours, independent from

the dose administered

• Phase I intra-thecal administration of rituximab (anti-CD20)– Rapid clearance from the CSF

Braen, Int J Toxicol 2010Rubenstein, Blood 2013

• Receptors FcRn = efflux

• Rat model, after direct intra-cranial administration

of a monoclonal IgG1

Cooper, Brain Res 2013

Perspectives

• Chemical modification of the Fc fragment

• Engineered Fab fragment antibodies