Forimtamig, a novel GPRC5D-targeting T-cell bispecific antibody with a 2+1 format, for the treatment of multiple myeloma
Abstract
Abstract Despite several approved therapies, multiple myeloma (MM) remains an incurable disease with high unmet medical need. “Off-the-shelf” T-cell bispecific antibodies (TCBs) targeting B-cell maturation antigen (BCMA) and G protein–coupled receptor class C group 5 member D (GPRC5D) have demonstrated high objective response rates in heavily pretreated patients with MM; however, primary resistance, short duration of response, and relapse driven by antigen shift frequently occur. Although GPRC5D represents the most selective target in MM, recent findings indicate antigen loss occurs more frequently than with BCMA. Thus, anti-GPRC5D immunotherapies must hit hard during a short period of time. Here, we characterize forimtamig, a novel GPRC5D-targeting TCB with 2+1 format. Bivalent binding of forimtamig to GPRC5D confers higher affinity than classical 1+1 TCB formats correlating with formation of more stable immunological synapses and higher potency in tumor cell killing and T-cell activation. Using an orthotopic mouse model of MM, forimtamig recruited T effector cells to the bone marrow and induced rapid tumor killing even after the introduction of step-up dosing to mitigate cytokine release. Combination of forimtamig with standard-of-care agents including anti-CD38 antibodies, immunomodulatory drugs, and proteasome inhibitors improved depth and duration of response. The combination of forimtamig with novel therapeutic agents including BCMA TCB and cereblon E3 ligase modulatory drugs was potent and prevented occurrence of GPRC5D -negative tumor relapse. Forimtamig is currently being evaluated in phase 1 clinical trials in patients with relapsed and refractory MM for monotherapy and in combination treatments. This trial was registered at www.ClinicalTrials.gov as #NCT04557150.
Article Details
Authors (46)
Jan Eckmann
1Discovery Oncology, Roche Pharma Research and Early Development, Roche Innovation Center, Munich, Germany
Tanja Fauti
2Discovery Oncology, Roche Pharma Research and Early Development, Roche Innovation Center, Zurich, Switzerland
Marlene Biehl
2Discovery Oncology, Roche Pharma Research and Early Development, Roche Innovation Center, Zurich, Switzerland
Aintzane Zabaleta
Cancer Center Clinica Universidad de Navarra (CCUN), Centro de Investigacion Medica Aplicada (CIMA), Instituto de Investigacion Sanitaria de Navarra (IdiSNA), CIBER-ONC number CB16/12/00369, Pamplona, Spain, Pamplona, Spain
Laura Blanco
3Clínica Universidad de Navarra, Centro de Investigación Médica Aplicada, University of Navarra, Pamplona, Spain
Iva Lelios
4Discovery Oncology, Roche Pharma Research and Early Development, Roche Innovation Center, Basel, Switzerland
Stefan Gottwald
1Discovery Oncology, Roche Pharma Research and Early Development, Roche Innovation Center, Munich, Germany
Richard Rae
1Discovery Oncology, Roche Pharma Research and Early Development, Roche Innovation Center, Munich, Germany
Stefanie Lechner
1Discovery Oncology, Roche Pharma Research and Early Development, Roche Innovation Center, Munich, Germany
Christa Bayer
1Discovery Oncology, Roche Pharma Research and Early Development, Roche Innovation Center, Munich, Germany
Quincy Dekempe
1Discovery Oncology, Roche Pharma Research and Early Development, Roche Innovation Center, Munich, Germany
Franz Osl
1Discovery Oncology, Roche Pharma Research and Early Development, Roche Innovation Center, Munich, Germany
Nadège Carrié
1Cancer Research Center of Toulouse (CRCT), Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS), Université Toulouse III-Paul Sabatier (UPS), Toulouse, France
Sahar Kassem
5Cancer Research Center of Toulouse, INSERM, Centre National de la Recherche Scientifique, Université Toulouse III-Paul Sabatier, Toulouse, France
Stefan Lorenz
Tony Christopeit
1Discovery Oncology, Roche Pharma Research and Early Development, Roche Innovation Center, Munich, Germany
Alejandro Carpy
1Discovery Oncology, Roche Pharma Research and Early Development, Roche Innovation Center, Munich, Germany
Alexander Bujotzek
1Discovery Oncology, Roche Pharma Research and Early Development, Roche Innovation Center, Munich, Germany
Ann-Marie Bröske
1Discovery Oncology, Roche Pharma Research and Early Development, Roche Innovation Center, Munich, Germany
Iryna Dekhtiarenko
2Discovery Oncology, Roche Pharma Research and Early Development, Roche Innovation Center, Zurich, Switzerland
Jan Attig
Leo Kunz
2Discovery Oncology, Roche Pharma Research and Early Development, Roche Innovation Center, Zurich, Switzerland
Floriana Cremasco
2Discovery Oncology, Roche Pharma Research and Early Development, Roche Innovation Center, Zurich, Switzerland
Roberto Adelfio
2Discovery Oncology, Roche Pharma Research and Early Development, Roche Innovation Center, Zurich, Switzerland
Georg Fertig
1Discovery Oncology, Roche Pharma Research and Early Development, Roche Innovation Center, Munich, Germany
Stefan Dengl
1Discovery Oncology, Roche Pharma Research and Early Development, Roche Innovation Center, Munich, Germany
Christian Gassner
1Discovery Oncology, Roche Pharma Research and Early Development, Roche Innovation Center, Munich, Germany
Felix Bormann
1Discovery Oncology, Roche Pharma Research and Early Development, Roche Innovation Center, Munich, Germany
Claudia Kirstenpfad
1Discovery Oncology, Roche Pharma Research and Early Development, Roche Innovation Center, Munich, Germany
Thomas Kraft
1Discovery Oncology, Roche Pharma Research and Early Development, Roche Innovation Center, Munich, Germany
Sarah Diggelmann
2Discovery Oncology, Roche Pharma Research and Early Development, Roche Innovation Center, Zurich, Switzerland
Melanie Knobloch
2Discovery Oncology, Roche Pharma Research and Early Development, Roche Innovation Center, Zurich, Switzerland
Carina Hage
1Discovery Oncology, Roche Pharma Research and Early Development, Roche Innovation Center, Munich, Germany
Romi Feddersen
1Discovery Oncology, Roche Pharma Research and Early Development, Roche Innovation Center, Munich, Germany
Gordon Heidkamp
1Discovery Oncology, Roche Pharma Research and Early Development, Roche Innovation Center, Munich, Germany
Thomas Pöschinger
1Discovery Oncology, Roche Pharma Research and Early Development, Roche Innovation Center, Munich, Germany
Maud Mayoux
Luise Bernasconi
7Lonza AG, Basel, Switzerland
Felipe Prosper
Charles Dumontet
8Cancer Research Center of Lyon, INSERM 1052/ Centre National de la Recherche Scientifique 5286/University of Lyon/Hospices Civils de Lyon, Lyon, France
Ludovic Martinet
1Cancer Research Center of Toulouse (CRCT), Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS), Université Toulouse III-Paul Sabatier (UPS), Toulouse, France
Stéphane Leclair
1Discovery Oncology, Roche Pharma Research and Early Development, Roche Innovation Center, Munich, Germany
Wei Xu
Bruno Paiva
Christian Klein
Pablo Umaña
1Roche Innovation Center Zurich, Roche Pharma Research and Early Development, Schlieren, Switzerland