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  • 12.03 ISB 1442, a first-in-class CD38 and CD47 bispecific antibody innate cell modulator for the treatment of CD38 positive hematological malignancies

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Oral Presentations
Plenary symposium 12: combination therapy (with a special focus on local IO)
12.03 ISB 1442, a first-in-class CD38 and CD47 bispecific antibody innate cell modulator for the treatment of CD38 positive hematological malignancies
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  1. C Grandclement1,
  2. C Estoppey1,
  3. E Dheilly1,
  4. M Panagopoulou1,
  5. E Martini1,
  6. V Labanca1,
  7. S De Angelis1,
  8. J Frei1,
  9. A Drake1,
  10. A Rubod1,
  11. G Gudi2,
  12. V Udupa3,
  13. J Olsen4,
  14. R Giovannini4,
  15. M Doucey1,
  16. E Feldman2,
  17. C Konto2,
  18. A Srivastava1,
  19. E Zhukovsky1,
  20. M Perro1 and
  21. S Sammicheli5
  1. 1Ichnos Sciences, Lausanne, Switzerland
  2. 2Ichnos Sciences, New York, NY, USA
  3. 3GLENMARK PHARMACEUTICALS, Mahape, India
  4. 4Ichnos Sciences, La Chaux-de-Fonds, Switzerland
  5. 5Ichnos Sciences, Epalinges, Switzerland

Abstract

Background ISB 1442 is a fully human first-in-class 2+1 biparatopic bispecific antibody targeting CD38 x CD47 using the BEAT® 2.0 (Bispecific Engagement by Antibodies based on the TCR) platform to target CD38 and CD47 as a treatment for CD38+ malignancies. ISB 1442 is designed with a bi-paratopic anti-CD38 arm that strongly binds two CD38 epitopes on tumor cells which do not functionally compete with daratumumab. The anti-CD47 arm is made of a single Fab designed to block interaction between CD47 and the signal-regulatory protein alpha (SIRPα) with low affinity. This approach enables CD47 binding only of proximal receptors on the same cell via avidity-induced binding of CD38 on tumor cells which is expected to induce minimal unintended effects on red blood cells (RBC) compared to anti-CD47 monoclonal antibody (mAb). The Fc portion of ISB 1442 is engineered to enhance antibody dependent cell phagocytosis (ADCP), antibody dependent cell cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC).

Materials and Methods ISB 1442 was tested for its capacity in vitro to induce ADCP, ADCC and CDC across a broad range of tumor cell lines expressing different levels of CD38 and CD47 relative. To assess the complex mechanisms of action of ISB 1442 in a single system, a multiple mode of action of killing (MMoAK) assay was established to allow for simultaneous killing by natural killer cells (ADCC), autologous macrophages (ADCP), and complement from human serum (CDC). In vivo, ISB 1442 was assessed in therapeutic tumor models, expressing high or low CD38 level, of subcutaneously established xenograft in CB17/SCID mice. On-target specificity was evaluated in vitro in human whole blood assays.

Results In vitro, ISB 1442 exhibited higher killing potency compared to daratumumab across a range of CD38-expressing tumor cells. Additionally, ISB 1442 showed in vitro tumor killing potency through phagocytosis comparable to anti-CD47 (5F9) mAb, acting mostly through ADCP. In the CDC, ADCC and MMoAK assays, ISB 1442 exhibited tumor cell killing that was twice as high as daratumumab in MM cell lines. In vivo, ISB 1442 induced higher tumor growth inhibition than daratumumab. ISB 1442 did not cause any detectable RBC depletion or binding to RBC suggesting a more favorable on-target specificity profile in humans as compared to anti-CD47 (5F9) mAb.

Conclusions We report a novel approach for the treatment for CD38 positive hematologic malignancies by co-targeting CD38 and CD47 using a first in class multispecific antibody. Based on its unique design and multiple mechanisms of action, ISB 1442 is anticipated to enhance antitumor activity in patients relative to anti-CD38 mAbs by overcoming primary and acquired tumor escape mechanisms of resistance.

Disclosure Information C. Grandclement: A. Employment (full or part-time); Significant; Ichnos Sciences. C. Estoppey: A. Employment (full or part-time); Significant; Ichnos Sciences. E. Dheilly: A. Employment (full or part-time); Significant; Ichnos Sciences. M. Panagopoulou: A. Employment (full or part-time); Significant; Ichnos Sciences. E. Martini: A. Employment (full or part-time); Significant; Ichnos Sciences. V. Labanca: A. Employment (full or part-time); Significant; Ichnos Sciences. S. De Angelis: A. Employment (full or part-time); Significant; Ichnos Sciences. J. Frei: A. Employment (full or part-time); Significant; Ichnos Sciences. A. Drake: A. Employment (full or part-time); Significant; Ichnos Sciences. A. Rubod: A. Employment (full or part-time); Significant; Ichnos Sciences. G. Gudi: A. Employment (full or part-time); Significant; Ichnos Sciences. V. Udupa: A. Employment (full or part-time); Significant; GLENMARK PHARMACEUTICALS LIMITED. J. Olsen: A. Employment (full or part-time); Significant; Ichnos Sciences. R. Giovannini: A. Employment (full or part-time); Significant; Ichnos Sciences. M. Doucey: A. Employment (full or part-time); Significant; Ichnos Sciences. E. Feldman: A. Employment (full or part-time); Significant; Ichnos Sciences. C. Konto: A. Employment (full or part-time); Significant; Ichnos Sciences. A. Srivastava: A. Employment (full or part-time); Significant; Ichnos Sciences. E. Zhukovsky: A. Employment (full or part-time); Significant; Ichnos Sciences. M. Perro: A. Employment (full or part-time); Significant; Ichnos Sciences. S. Sammicheli: A. Employment (full or part-time); Significant; Ichnos Sciences.

http://dx.doi.org/10.1136/jitc-2022-ITOC9.10

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