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Printable Handouts
Navigable Slide Index
- Introduction
- Summary
- The antibody revolution
- Currently approved mAbs for cancer
- Many antibodies are directed to the same target
- Rituximab the archetypal B-cell targeting mAb
- How do direct targeting mAb work?
- Key mediators of mAb efficacy FcγRs
- Consequences of FcγR ligation
- Dissection of mechanism
- Macrophages mediate mAb therapy via activatory FcγR
- Direct targeting mAb
- Still room for improvement
- Rituximab internalises in human cells
- Correlated with response to Rituximab in different NHL
- Internalisation correlates with FcγRIIb expression
- Current scenario with rituximab
- What is the impact of internalisation?
- Internalisation limits all 3 effector functions
- This phenomenon could cause resistance of NHL to rituximab therapy
- PFS in lymphoma patients
- How do we improve responses?
- B cell deletion as a paradigm for mAb development
- Alternative anti-CD20 mAb
- CD20 mAb depletion of circulating B cells
- Type II use the same effector mechanism
- Type II not internalised in lymphoma
- Confirmation in a mouse tumour model (EuTCL-1)
- OBZ is more than just a type II
- Impact of glyco-engineering on OBZ
- OBZ exhibits higher ADCC potency than rituximab
- Confirmation in human models
- Obinutuzumab is better BUT still requires improvement
- Tumour induces changes to the microenvironment
- Tumour extrinsic factors: Tumour alters FcγR expression
- Tumour reduces A:I ratio on macrophages
- Strategies to overcome deletion resistance
- The combination of idelalisib and rituximab
- BH3-mimetics
- Combination of OBZ with venetoclax in CLL samples
- Strategies to overcome deletion resistance
- Block FcγRIIB
- Immunomodulatory mAb
- Co-signalling interactions in T Cells
- Immunomodulatory mAbs
- What about in haematology?
- Early conclusions for immunomodulatory mAb
- Therapeutic synergy of anti-CD20 and anti-CD27 (1)
- Therapeutic synergy of anti-CD20 and anti-CD27 (2)
- Take-home messages
- Acknowledgments
Topics Covered
- Introduction to the development and clinical use of monoclonal antibodies (mAb) in haemato-oncology
- Currently approved mAb for treating cancer
- Direct targeting antibodies
- Rituximab
- Fc gamma receptors (FcgR) as key mediators of cellular immunity
- Macrophages as key effector cells
- B cell deletion as a paradigm for mAb effects
- Type I versus Type II antibodies
- Obinutuzumab
- Hematological malignancies
- Immunomodulatory mAb
- Combinations between direct targeting and immunomodulatory mAb
Links
Series:
Categories:
Therapeutic Areas:
Talk Citation
Cragg, M. (2020, May 31). Monoclonal antibodies in haemato-oncology [Video file]. In The Biomedical & Life Sciences Collection, Henry Stewart Talks. Retrieved November 21, 2024, from https://doi.org/10.69645/NUZY5220.Export Citation (RIS)
Publication History
Financial Disclosures
- Mark Cragg is a retained consultant for BioInvent International and has performed educational and advisory roles for Baxalta and Boehringer Ingleheim. He has received research funding from Roche, Gilead, Bioinvent International and GSK.
Other Talks in the Series: The Immune System - Key Concepts and Questions
Transcript
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0:00
I'm Professor Mark Cragg.
I'm a Professor of Experimental
Cancer Biology at the Center for
Cancer Immunology in Southampton.
And today,
I'm going to talk about "Monoclonal
Antibodies in Haemato- Oncology".
0:14
So as a brief introduction summary of what
I'm going to talk about today, in essence,
it's about the antibody
revolution where we've come from.
From a number of decades ago
where we had very few antibodies
in the treatment of medicine.
I'm going to give you
a case study in Rituximab,
which is the first monoclonal antibody
that's approved in haematology.
And in fact in all oncology, then I'm
going talk through some of the work that's
been done looking at the mechanisms
of action of monoclonal antibodies in
human oncology and the mechanisms of
resistance that we've now encountered.
And then, talking about some of the
strategies that we might use to try and
overcome that resistance and
that largely comes down to
using monoclonal antibodies
in various combinations.
And then, I'll have a little speculation
at the end in terms of the future and
where we're going with
some of these strategies.
1:02
So the antibody revolution really
started in the late 1990's.
In that decade really we'd got six
approved monoclonal antibodies.
Some of those were fully mouse monoclonals
and therefore had a limited utility
in humans, but
now we've got as high as over 70 approved
monoclonal antibodies that we use to
treat human beings for various diseases.
And the exciting thing is they're still
more in clinical development, and
soon to be approved.
So we have hundreds of monoclonal
antibodies in phase I and II trials and
a similar number, probably in phase III
trials that may get approved next year.
So we're looking at probably getting
to 100 in the next few years.